CN1771049A - 生长激素释放抑制因子-多巴胺嵌合类似物 - Google Patents
生长激素释放抑制因子-多巴胺嵌合类似物 Download PDFInfo
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Abstract
本发明公开了生长激素释放抑制因子-多巴胺嵌合类似物以及与其治疗瘤形成、肢端肥大症和其它疾病的应用有关的方法。
Description
背景技术
[001]本发明涉及生长激素释放抑制因子-多巴胺嵌合类似物以及与其治疗应用有关的方法。
[002]多巴胺是帕金森病和精神分裂症的发病机制中涉及的儿茶酚胺神经递质。多巴胺及相关分子在小鼠中显示出能抑制一些类型的恶性肿瘤的生长,这种活性被不同地归因于对肿瘤细胞增生的抑制,对肿瘤免疫的刺激或在恶性黑色瘤中对黑色素代谢的影响。最近的研究表明在内皮细胞上存在D2多巴胺受体。最近报导多巴胺以非毒性水平强烈地和选择性地抑制VPF/VEGF的血管渗透性和血管原性活性。
[003]一种十四肽——生长激素释放抑制因子(SS)在组织中如脑下垂体、胰和胃肠道中对不同的分泌过程具有有效的抑制作用。SS在中枢神经系统中也可作为神经调节物。SS的这些在本质上都具有抑制作用的生物学效果是通过一系列G蛋白偶联受体引起,其中的五种不同亚型已经被表征(SSTR1-SSTR5)。这五种亚型对内生的SS配体具有相似的亲和性,但在不同的组织中具有不同的分布。生长激素释放抑制因子与五个不同的受体亚型以较高的和相等的亲和性进行结合。
[004]有证据表明,通过由SSTR-1,-2,-3,-4和-5亚型阻止细胞生长,和/或通过SSTR-3亚型诱导凋亡作用,SS可调节细胞增生。SS和各种类似物已经显示出在活体内和体外通过特定的SS受体(SSTR’s)以及可能不同的受体后反应来抑制正常细胞和瘤细胞的增生。另外,有证据表明,不同的SSTR亚型在正常人体组织和瘤组织中进行表达,因而组织对不同的SS类似物具有不同亲和性,以及对它们的治疗效果具有不同的临床反应。
[005]不同类型的生长激素释放抑制因子受体亚型的结合与多种病症和/或疾病的治疗相关。例如,对生长激素的抑制归因于生长激素释放抑制因子2-型受体(SSTR2),而对胰岛素的抑制则归因于生长激素释放抑制因子5-型受体(“SSTR5”)。2型和5型的活化与生长激素的抑制有关,尤其与生长激素分泌腺瘤(肢端肥大症)和促甲状腺激素(TSH)分泌腺瘤有关。对5型而并非2型的活化与治疗催乳素分泌腺瘤相关。其它与生长激素释放因子受体亚型的活化相关的适应症包括对用于治疗糖尿病、血管病、增生性视网膜炎、黎明现象(dawn Phenomenon)和肾病的胰岛素和/或胰增血糖素进行抑制;抑制胃酸分泌并尤其是抑制消化器官溃疡,肠皮肤(enterocutaneous)和胰腺皮肤(pancreaticocutaneous)瘘管、过敏性肠综合症、倾倒综合症、含水腹泻综合症、与AIDS相关的腹泻、化疗引发的腹泻、急性和慢性胰腺炎和胃肠激素分泌肿瘤;治疗癌症如肝细胞瘤;抑制血管生成;治疗炎性疾病如关节炎、视网膜炎、慢性同种异体抑制排斥、血管成形术;防止脉管移植和胃肠出血。优选的生长激素释放因子类似物对特定的生长激素释放因子受体亚型具有选择性,或对能得到所希望的生物学反应的亚型具有选择性,因此能减少与其它会导致不希望的副作用的受体亚型进行反应。
[006]生长激素释放因子(SS)和其受体(SSTR1-SSTR5)在正常的人体滤泡旁(parafollicular)C细胞和髓状甲状腺癌(MTC)中进行表达。MTC是一种由产生降钙素(CT)、生长激素抑制因子以及一些其它的肽的甲状腺滤泡旁C细胞引起的肿瘤。最近证明了SS和SSTR’S在人类MTC中表达,且表明了SS和其类似物引起了血浆CT水平下降,使MTC病人的症状得以改善。另一个近期的研究表明SS和其类似物,尤其是SSTR-1和SSTR-2可抑制肿瘤细胞的增生,这暗示了特定的SSTR亚型在调节MTC细胞生长的方面起到了作用。选择性地作用于MTC细胞生长的SSTR亚型类似物的发展和表征对临床和治疗应用是有利的。
发明概述
[007]本发明基于发现了生长激素释放抑制因子-多巴胺嵌合类似物,该嵌合类似物包括既保留生长激素释放抑制因子活性又保留多巴胺活性的化合物。本发明的嵌合类似物被认为是有用的,如用作体外的研究工具,诊断化验等,或用作体内的诊断或治疗剂。与天然的生长激素释放抑制因子和多巴胺单独相比或与其组合相比,本发明中优选的嵌合类似物具有提高的活性。
[008]因此,本发明的第一方面公开了一种嵌合类似物或其药学上可接受的盐,该嵌合类似物包括(1)与一个或多个生长激素释放抑制因子受体相结合的至少一个结构部分,以及(2)与一个或多个多巴胺受体相结合的至少一个结构部分。
[009]在第一方面的第一种实施方式中,该嵌合类似物包括式(I)结构,
其中,
[010]X是H,Cl,Br,I,F,-CN,C1-10烷基,C1-10杂烷基,C2-10烯基,C2-10炔基,取代的C1-10烷基,取代的C1-10杂烷基,取代的C2-10烯基,或取代的C2-10炔基;
[0011]R1是H,C1-10烷基,C1-10杂烷基,C2-10烯基,C2-10炔基,取代的C1-10烷基,取代的C1-10杂烷基,取代的C2-10烯基,取代的C2-10炔基,或-CN;
[0012]R2和R3各自独立地为H或不存在,条件是当R2和R3都不存在时,它们所连接的碳原子之间存在双键;
[0013]R4是H,C1-10烷基,C1-10杂烷基,C2-10烯基,C2-10炔基,取代的C1-10烷基,取代的C1-10杂烷基,取代的C2-10烯基,或取代的C2-10炔基;
[0014]Y是-O-,-C(O)-,-S-,-S-(CH2)s-C(O)-,-S(O)-,-S(O)2-,-SC(O)-,-OC(O)-,-N(R5)-C(O)-,或-N(R6)-;
[0015]当Y是-S-,-S(O)-,-S(O)2-,-O-或-N(R6)-时,L是-(CH2)p-C(O)-;或者,当Y是-N(R6)-,-O-,或-S-时,L是-C(O)-(CR7R8)q-C(O)-;或者,当Y是-C(O)-,SC(O)-,-OC(O)-,-S-(CH2)s-C(O)-,或-N(R5)-C(O)-时,L是(氨基酸)t;
[0016]W是-CR9,R10-;
[0017]R5和R6各自独立地为H,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基,或取代的烷基芳基;
[0018]R7,R8,R9和R10各自独立地为H,F,Cl,Br,I,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基,或取代的烷基芳基;或者,R7和R8可任选连接在一起而形成环体系;或者,R9和R10可任选连接在一起而形成环体系;
[0019]i是1-10,条件是当i为1时,R1不为H、C1-4烷基、烯丙基、烯基或-CN,R4不为H或-CH3,R5、R6、R7和R8各自独立且不为H或C1-5烷基,L不为-(Doc)t-,X不为H、Cl、Br、I、F、-CN或C1-5烷基,或R9和R10各自独立且不为H;
[0020]m是0或1;
[0021]n是0-10;
[0022]p是1-10;
[0023]q是1-5;
[0024]s是1-10;
[0025]t是1-10;
[0026]Z是至少一种生长激素释放抑制因子受体的配体;
[0027]或其药学上可接受的盐;以及
[0028]其中,括号之间的每一个结构在每次出现时均独立地连接到Z的N-末端或内部的氨基基团或羟基基团上。
[0029]在第一方面的第二种实施方式,该嵌合类似物包括式(II)结构,
其中,
[0030]X是H,Cl,Br,I,F,-CN,C1-10烷基,C1-10杂烷基,C2-10烯基,C2-10炔基,取代的C1-10烷基,取代的C1-10杂烷基,取代的C2-10烯基,或取代的C2-10炔基;
[0031]R1是H,C1-10烷基,C1-10杂烷基,C2-10烯基,C2-10炔基,取代的C1-10烷基,取代的C1-10杂烷基,取代的C2-10烯基,取代的C2-10炔基,或-CN;
[0032]R2和R3各自独立地为H或不存在,条件是当R2和R3不存在时,它们所连接的碳原子之间存在双键;
[0033]R4是H,C1-10烷基,C1-10杂烷基,C2-10烯基,C2-10炔基,取代的C1-10烷基,取代的C1-10杂烷基,取代的C2-10烯基,或取代的C2-10炔基;
[0034]R5是H,C1-10烷基,C1-10杂烷基,C2-10烯基,C2-10炔基,取代的C1-10烷基,取代的C1-10杂烷基,取代的C2-10烯基,取代的C2-10炔基,或式-(CH2)rN(R11,R12)表示的基团;
[0035]Y是-O-,-C(O)-,-S-,-SC(O)-,-OC(O)-,-N(R6)-C(O)-,-N(R7)-,或-N(R8)-(CH2)s-C(O)-;
[0036]当Y是-S-,-O-或-N(R7)-时,L是-(CH2)p-C(O)-;或者,当Y是-N(R7)-,-O-,或-S-时,L是-C(O)-(CR9R10)q-C(O)-;或者,当Y是-C(O)-,SC(O)-,-OC(O)-,-N(R8)-(CH2)s-C(O)-,或-N(R6)-C(O)-时,L是(氨基酸)t;
[0037]W是-CR9,R10-;
[0038]R6,R7和R8各自独立地为H,C1-10烷基,取代的C1-10烷基,C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基,或取代的烷基芳基;
[0039]R9和R10各自独立地为H,Cl,Br,I,F,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基,或取代的烷基芳基;或者,R9和R10可任选地连接在一起形成环体系;
[0040]R11和R12各自独立地为H,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基,或取代的烷基芳基;
[0041]i是1-10,条件是当i为1时,R1不为H、C1-4烷基、烯丙基、烯基或-CN,R4不为H或-CH3,R5不为C1-5烷基基团或式-(CH2)rN(CH3)v的基团,R6,R7,R8,R9和R10各自独立且不为H或C1-5烷基,L不为-(Doc)t-,或者X不为H,Cl,Br,I,F,-CN,或C1-5烷基;
[0042]m是0或1;
[0043]n是2-10;
[0044]p是1-10;
[0045]q是1-5;
[0046]r是1-8;
[0047]s是1-10;
[0048]t是1-10;
[0049]v是2-4;
[0050]Z是至少一种生长激素释放抑制因子受体的配体;或
[0051]其药学上可接受的盐;以及
[0052]其中,括号之间的每一个结构在每次出现时均独立地连接到Z的N-末端或内部的氨基基团或羟基基团上。
[0053]在第一方面的第三种实施方式,权利要求1的嵌合类似物中,所述嵌合类似物包括式(III)结构,
其中,
[0054]R2是H,-N(R11)N(R12,R13),-N(R6R7)或-COOH;
[0055]R4和R5各自独立地为H,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基,取代的烷基芳基或R8-C(O)-;
[0056]W是-CR9R10-或-(CH2)q-NH-(CH2)r-;
[0057]R1,R6,R7,R8,R11,R12和R13各自独立地为H,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
[0058]R9和R10各自独立地为H,-OH,-CN,-NO2,F,Cl,Br,I,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,烷基芳基,取代的烷基芳基或芳基;
[0059]X是C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,烷基芳基,取代的烷基芳基,芳基或酰基;
[0060]Q是C或N;条件是当Q是N时,R2不存在;
[0061]i是1-10;
[0062]n是1-6;
[0063]q是1-6;
[0064]r是1-8;
[0065]Z是至少一种生长激素释放抑制因子受体的配体;或者
[0066]其药学上可接受的盐;以及
[0067]其中,括号之间的每一个结构在每次出现时均独立地连接到Z的N-末端或内部的氨基基团或羟基基团上。
[0068]在第一方面的第四种实施方式中,该嵌合类似物包括式(IV)结构,
其中,
[0069]R1和R2各自独立地为H,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
[0070]R3,R4,R5,R6和R7各自独立地为H,-OH,-CN,-NO2,F,Cl,Br,I,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
[0071]W是-CR4R5-;
[0072]Y是-(CR6R7)m-C(O)-或酰基;
[0073]m是0-10;
[0074]n是1-6;
[0075]Z是至少一种生长激素释放抑制因子受体的配体;或者
[0076]其药学上可接受的盐;以及
[0077]其中,括号之间的每一个结构在每次出现时均独立地连接到Z的N-末端或内部的氨基基团或羟基基团上。
[0078]在第一方面的第五种实施方式中,该嵌合类似物包括式(V)结构,
其中,
[0079]P是-N(R3R4)或H;
[0080]X是N或S;
[0081]W是-CR5R6-;
[0082]Y是-(CR7R8)m-C(O)-;
[0083]R1,R3和R4各自独立地为H,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
[0084]R2,R5,R6,R7和R8各自独立地为H,-OH,-CN,-NO2,F,Cl,Br,I,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
[0085]i是1-10;
[0086]m是0-10;
[0087]n是0-6;
[0088]Z是至少一种生长激素释放抑制因子受体的配体;或者
[0089]其药学上可接受的盐;以及
[0090]其中,括号之间的每一个结构在每次出现时均独立地连接到Z的N-末端或内部的氨基基团或羟基基团上。
[0091]在第一方面的第六种实施方式,该嵌合类似物包括式(VI)结构,
其中,
[0092]Y是-(CR2R3)m-C(O)-或酰基;
[0093]R1是H,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
[0094]R2和R3各自独立地为H,-OH,-CN,-NO2,F,Cl,Br,I,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
[0095]i是1-10;
[0096]m是0-10;
[0097]Z是至少一种生长激素释放抑制因子受体的配体;或者
[0098]其药学上可接受的盐;以及
[0099]其中,括号之间的每一个结构在每次出现时均独立地连接到Z的N-末端或内部的氨基基团或羟基基团上。
[0100]在第一方面的第七种实施方式中,该嵌合类似物包括式(VII)结构,
其中,
[0101]P是-N(R3R4)或H;
[0102]L是-(CR5R6)m-C(O)-或酰基;
[0103]Y是C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基,取代的烷基芳基或不存在;
[0104]R1,R2,R5和R6各自独立地为H,-OH,-CN,-NO2,F,Cl,Br,I,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
[0105]R3和R4各自独立地为H,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
[0106]i是1-10;
[0107]m是0-10;
[0108]Z是至少一种生长激素释放抑制因子受体的配体;或者
[0109]其药学上可接受的盐;以及
[0110]其中,括号之间的每一个结构在每次出现时均独立地连接到Z的N-末端或内部的氨基基团或羟基基团上。
[0111]在第一方面的第八种实施方式中,该嵌合类似物包括式(VIII)结构,
其中,
[0112]X和Y各自独立地为-OH,-OR4或R5-C(O)-O-;
[0113]L是-(CR3R4)m-C(O)-或酰基;
[0114]R1,R2,R3和R4各自独立地为H,-OH,F,Cl,Br,I,-CN,NO2,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;或R2和R3可任选连接在一起而形成环体系;
[0115]R5是H,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
[0116]i是1-10;
[0117]m是0-10;
[0118]Z是至少一种生长激素释放抑制因子受体的配体;或者
[0119]其药学上可接受的盐;以及
其中,括号之间的每一个结构在每次出现时均独立地连接到Z的N-末端或内部的氨基基团或羟基基团上。
[0120]在第一方面的第九种实施方式中,该嵌合类似物包括式(IX)结构,
其中,
[0121]X和Y各自独立地为-OH,-OR4或R7-C(O)-;
[0122]Q是-(CR5R6)m-C(O)-或酰基;
[0123]R1,R2,R3,R4,R5和R6各自独立地为H,-OH,F,Cl,Br,I,-CN,NO2,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;或R1和R2可任选地连接在一起而形成环体系;或R3和R4可任选地连接在一起而形成环体系;
[0124]R7是H,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
[0125]i是1-10;
[0126]m是0-10;
[0127]Z是至少一种生长激素释放抑制因子受体的配体;或者
[0128]其药学上可接受的盐;以及
[0129]其中,括号之间的每一个结构在每次出现时均独立地连接到Z的N-末端或内部的氨基基团或羟基基团上。
[0130]在第一方面的第十方面,该嵌合类似物包括式(X)结构,
其中,
[0131]Y是-(CR8R9)m-C(O)-或酰基;
[0132]R1,R2,R3,R4,R5,R6,R7,R8和R9各自独立地为H,-OH,F,Cl,Br,I,-CN,NO2,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
[0133]i是1-10;
[0134]m是0-10;
[0135]Z是至少一种生长激素释放抑制因子受体的配体;或者
[0136]其药学上可接受的盐;以及
[0137]其中,括号之间的每一个结构在每次出现时均独立地连接到Z的N-末端或内部的氨基基团或羟基基团上。
[0138]在第一方面的另一种实施方式中,该嵌合类似物包括表1中所列的任何组合物或其药学上可接受的盐。
[0139]在第一方面的另一种实施方式中,该嵌合类似物包括下式的化合物:
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Ac-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Ac-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-31Tyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,或
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2;或
其药学上可接受的盐。
[0140]在第一方面的优选实施方式中,该嵌合类似物包括下式的化合物:
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2或
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2;或
其药学上可接受的盐。
[0141]在第一方面的更优选实施方式中,该嵌合类似物包括式Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2的化合物;或其药学上可接受的盐。在另一个优选实施方式中,该嵌合类似物包括式Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2的化合物;或其药学上可接受的盐。在又一个优选实施方式中,该嵌合类似物包括式Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2的化合物;或其药学上可接受的盐。
[0142]在第一方面的另一种实施方式中,该嵌合类似物包括下式的化合物:
Dop2-Lys(Dop2)-DTyr-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],
Dop2-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],或
Dop2-DTyr-DTyr-Caeg-环[DCys-3Pal-DTrp-Lys-Dcys]-Thr(Bzl)-Tyr-NH2;或
其药学上可接受的盐。
[0143]本发明的第二方面公开了一种在化学合成中用作中间体的化合物,其中所述的中间体包括如下所示的式(3),(6),(11),(14),(18),(21),(24)或(27)的化合物(本文中分别称作中间体化合物(3),(6),(11),(14),(18),(21),(24)和(27)):
;或
或其有机盐或无机盐。
[0144]本发明的第三方面公开了一种在需要的患者体内引起多巴胺受体激动作用的方法,其中所述的方法包括以有效量的本发明嵌合类似物向所述的患者给药,其中所述的嵌合类似物包括式(I),(II),(III),(IV),(V),(VI)(VII),(VIII),(IX)或(X)的化合物或其药学上可接受的盐;或中间体化合物(3),(6),(11),(14),(18),(21),(24)或(27)或其有机盐或无机盐;以及其中所述的有效量是能在所述的患者体内有效地引起多巴胺受体激动作用的用量。
[0145]在第三方面的第一种实施方式中,该嵌合类似物包括表1所列的任何化合物;或其药学上可接受的盐。
[0146]在第三方面的第二种实施方式中,该嵌合类似物包括下式的化合物:
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Ac-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Ac-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,或
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2;或
其药学上可接受的盐。
[0147]在一种优选的实施方式中,该嵌合类似物包括下式的化合物:
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,或
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2;或
其药学上可接受的盐。
[0148]在第三方面一种更优选的实施方式中,该嵌合类似物包括式Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2的化合物;或其药学上可接受的盐。
[0149]在第三方面的另一种更优选实施方式中,该嵌合类似物包括式Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2的化合物;或其药学上可接受的盐。在第三方面的另一种更优选实施方式中,嵌合类似物包括式Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2的化合物;或其药学上可接受的盐。在第三方面的第三种实施方式中,嵌合类似物包括下式的化合物:
Dop2-Lys(Dop2)-DTyr-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],
Dop2-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],或
Dop2-DTyr-DTyr-Caeg-环[DCys-3Pal-DTrp-Lys-Dcys]-Thr(Bzl)-Tyr-NH2;或
其药学上可接受的盐。
[0150]本发明的第四方面公开了一种在需要的患者体内引起生长激素释放抑制因子受体激动作用的方法,其中所述的方法包括以有效量的本发明嵌合类似物向所述患者给药,其中所述的嵌合类似物包括式(I),(II),(III),(IV),(V),(VI)(VII),(VIII),(IX)或(X)的化合物或其药学上可接受的盐;或中间体化合物(3),(6),(11),(14),(18),(21),(24)或(27)或其有机盐或无机盐;以及其中所述的有效量为能在所述患者体内有效地引起生长激素释放抑制因子受体激动作用的用量。
[0151]在第四方面的第一实施方式中,该嵌合类似物包括表1中所列的任何化合物;或其药学上可接受的盐。
[0152]在第四方面的第二实施方式中,该嵌合类似物包括下式的化合物:
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Ac-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Ac-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,或
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2;或
其药学上可接受的盐。
[0153]在一种优选的实施方式中,该嵌合类似物包括下式的化合物:
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,或
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2;或
其药学上可接受的盐。
[0154]在第四方面一种更优选的方式中,该嵌合类似物包括式Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2的化合物;或其药学上可接受的盐。在第四方面一种更优选的实施方式中,该嵌合类似物包括式Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2的化合物;或其药学上可接受的盐。在第四方面另一种更优选的方式中,嵌合类似物包括式Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2的化合物;或其药学上可接受的盐。
[0155]在第四方面的第三实施方式中,该嵌合类似物包括下式的化合物:
Dop2-Lys(Dop2)-DTyr-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],
Dop2-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],或
Dop2-DTyr-DTyr-Caeg-环[DCys-3Pal-DTrp-Lys-Dcys]-Thr(Bzl)-Tyr-NH2;或
其药学上可接受的盐。
[0156]本发明的第五方面公开了一种在需要的患者体内既引起多巴胺受体激动作用又引起生长激素释放抑制因子受体激动作用的方法,其中所述的方法包括以有效量的本发明嵌合类似物向所述的患者给药,其中所述的嵌合类似物包括式(I),(II),(III),(IV),(V),(VI)(VII),(VIII),(IX)或(X)的化合物或其药学上可接受的盐;或中间体化合物(3),(6),(11),(14),(18),(21),(24)或(27)或其有机盐或无机盐;以及其中所述的有效量为能在所述患者体内有效地引起多巴胺受体和生长激素释放抑制因子受体激动作用的用量。
[0157]在第五方面的第一实施方式中,该嵌合类似物包括表1所列的任意化合物;或其药学上可接受的盐。
[0158]在第五方面的第二实施方式中,该嵌合类似物包括下式的化合物:
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Ac-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Ac-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,或
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2;
或
其药学上可接受的盐。
[0159]在优选实施方式中,该嵌合类似物包括下式的化合物:
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,或
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2;或
其药学上可接受的盐。
[0160]在第五方面的一种更优选方式中,该嵌合类似物包括式Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2的化合物;或其药学上可接受的盐。在第五方面另一种更优选方式中,嵌合类似物包括式Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2的化合物;或其药学上可接受的盐。在第五方面又一种优选方式中,嵌合类似物包括式Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2的化合物;或其药学上可接受的盐。
[0161]在第五方面的第三实施方式中,该嵌合类似物包括下式的化合物:
Dop2-Lys(Dop2)-DTyr-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],
Dop2-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],或
Dop2-DTyr-DTyr-Caeg-环[DCys-3Pal-DTrp-Lys-Dcys]-Thr(Bzl)-Tyr-NH2;或
其药学上可接受的盐。
[0162]本发明的第六方面公开了一种药物组合物,其包括有效量的式(I),(II),(III),(IV),(V),(VI)(VII),(VIII),(IX)或(X)的化合物或其药学上可接受的盐,;或中间体化合物(3),(6),(11),(14),(18),(21),(24)或(27)或其有机盐或无机盐;以及药学上可接受的载体中,其中所述的有效量是能在需要的患者体内有效地引起多巴胺受体激动作用或有效地引起生长激素释放抑制因子受体激动作用或有效地引起上述两种激动作用的用量。
[0163]在第六方面的第一实施方式中,该嵌合类似物包括表1中所列的任何化合物;或其药学上可接受的盐。
[0164]在第六方面的第二实施方式中,该嵌合类似物包括下式的化合物:
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Ac-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Ac-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,或
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2;或
其药学上可接受的盐。
[0165]在一种优选实施方式中,该嵌合类似物包括下式的化合物:
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,或
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2;或
其药学上可接受的盐。
[0166]在第六方面一种更优选的实施方式中,该嵌合类似物包括式Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2的化合物;或其药学上可接受的盐。在第六方面另一种更优选的方式中,嵌合类似物包括式Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2的化合物;或其药学上可接受的。在第六方面另一种优选的实施方式中,嵌合类似物包括式Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2的化合物;或其药学上可接受的盐。
[0167]在第六方面的第三种实施方式中,该嵌合类似物包括下式的化合物:
Dop2-Lys(Dop2)-DTyr-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],
Dop2-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],或
Dop2-DTyr-DTyr-Caeg-环[DCys-3Pal-DTrp-Lys-Dcys]-Thr(Bzl)-Tyr-NH2;或
其药学上可接受的盐。
[0168]本发明的第七方面公开了一种治疗患者所患有的疾病或病症的方法,所述方法包括以治疗有效量的嵌合类似物向所述患者给药,其中所述的嵌合类似物包括式(I),(II),(III),(IV),(V),(VI)(VII),(VIII),(IX)或(X)的化合物;表1中所列的任何化合物;
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Ac-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Ac-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],
Dop2-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],或
Dop2-DTyr-DTyr-Caeg-环[DCys-3Pal-DTrp-Lys-Dcys]-Thr(Bzl)-Tyr-NH2;或其药学上可接受的盐;或中间体化合物(3),(6),(11),(14),(18),(21),(24)或(27)或其有机盐或无机盐;以及其中所述的疾病或病症选择下列:神经内分泌肿瘤;血管疾病;结缔组织疾病;免疫性疾病;胃肠道,胰腺,肾脏或肝脏疾病;代谢性疾病;恶疾;肺部,乳腺,前列腺,肝脏,甲状腺,血癌或肿瘤;肌与骨胳疾病;恐慌症;和鸦片用药过量;以及其中所述的治疗有效量是指有效地治疗所述患者所患有的疾病或病症的用量。
[0169]在第七方面的第一实施方式中,神经内分泌肿瘤是垂体的神经内分泌肿瘤。在第一优选的方式中,垂体的神经内分泌肿瘤是产生ACTH的肿瘤。优选地,产生ACTH的肿瘤是Cushing’s疾病。在第二优选方式中,垂体的神经内分泌肿瘤是产生生长激素的肿瘤。优选地,产生生长激素的肿瘤是肢端肥大症。在第三优选方式中,垂体的神经内分泌肿瘤是产生催乳激素的肿瘤。优选地,产生催乳激素的肿瘤是催乳素瘤。在第四种优选方式中,垂体的神经内分泌肿瘤是高催乳素血症或催乳素血症。在第五种优选方式中,垂体的神经内分泌肿瘤是分泌促甲状腺激素(TSH)的肿瘤。在第六种优选方式中,垂体的神经内分泌肿瘤是“无功能的”的垂体腺瘤。在第七种优选的方式中,垂体的神经内分泌肿瘤是促性腺素瘤。
[0170]在第七方面的第二个实施方式中,神经内分泌肿瘤是良性肿瘤。在一种优选实施方式中,良性肿瘤导致类癌综合症。在第七方面的第三个实施方式中,神经内分泌肿瘤是胰升糖素瘤。在第七方面的第四个实施方式中,神经内分泌肿瘤是小细胞肺癌。在第七方面的第五个实施方式中,神经内分泌肿瘤是甲状腺髓样癌。在第七方面的第六个实施方式中,神经内分泌肿瘤是is VIP肿瘤。在第七方面的第七个实施方式中,神经内分泌肿瘤是胰岛素瘤。在第七方面的第八个实施方式中,所述血管疾病是不适当的血管生成。在第七方面的第九个实施方式中,所述血管疾病是再狭窄。在第七方面的第十个实施方式中,所述血管疾病是视网膜病。在一种优选实施方式中,视网膜病是糖尿病性视网膜病或增生性视网膜病。在另一种优选实施方式中,视网膜病是黄斑变性,优选为与年龄相关的黄斑变性。
[0171]在第七方面的另一个实施方式中,结缔组织疾病是硬皮病。在第七方面的另一个实施方式中,免疫性疾病是风湿性关节炎。在第七方面的再一个实施方式中,免疫性疾病是炎症。在第七方面的另一个实施方式中,免疫性疾病是纤维化。在第七方面的另一个实施方式中,免疫性疾病是Graves’眼病。在第七方面的另一个实施方式中,免疫性疾病是同种异体移植物排斥。在第七方面的另一个实施方式中,胃肠道疾病包括胃酸分泌,胃溃疡,炎症性肠病(IBD)或痢疾。在一个优选的实施方式中,IBD是肠易激综合症或Crohn’s疾病。在另一个优选方式中,痢疾是与AIDS相关的或与化疗相关的或水状痢疾综合症。在另一个优选方式中,胃肠道疾病是小肠综合症,小肠梗阻,胃食道反流,十二指肠胃反流,H.幽门增生或胃肠出血。
[0172]在第七方面的另一个实施方式中,代谢性疾病包括高脂血症,胰岛素抵抗力,X综合症,肥胖症,糖尿病或糖尿病相关性疾病。在一个优选实施方式中,糖尿病相关性疾病包括糖尿病性肾病,糖尿病性神经病,糖尿病性视网膜病或胃轻瘫。
[0173]在第七方面的另一个实施方式中,恶疾是指心脏恶疾,癌性恶疾或衰老性恶疾。
[0174]在第七方面的另一个实施方式中,疾病或病症包括神经胶质瘤,厌食症,甲状腺机能减退,Graves’疾病,高醛甾酮症,系统性硬化,胰腺炎,外部和内部胰腺假囊肿和腹水,胰皮肤瘘(pancreaticocutaneous fistula),nesidoblastosis,高胰岛素血症,胃泌素瘤,Zollinger-Ellison综合症,分泌胃肠激素的肿瘤,黎明现象(dawn phenomenon),倾倒综合症,甲状旁腺功能亢进症,Paget’s疾病,多囊卵巢疾病,直立性低血压,饭后低血压,门静脉高血压,血管病或移植血管流血。
[0175]在本发明以上公开的这一方面的第一相关的实施方式中,该嵌合类似物包括SSTR-1激动剂和多巴胺受体激动剂;或其药学上可接受的盐。在第一个优选实施方式中,该嵌合类似物还包括SSTR-2激动剂或SSTR-3激动剂或其药学上可接受的盐,或者两者都包含。
[0176]在第二种优选实施方式中,该嵌合类似物还包括SSTR-5激动剂或其药学上可接受的盐。在第三种优选实施方式中,该嵌合类似物还包括SSTR-2激动剂或SSTR-3激动剂或其药学上可接受的盐。
[0177]在一种更优选的方式中,该嵌合类似物包括SSTR-1激动剂和多巴胺受体激动剂,以及还进一步包括SSTR-2激动剂,SSTR-3激动剂,SSTR-5激动剂或其药学上可接受的盐。
[0178]在本发明以上公开的这一方面的第二种相关实施方式中,该嵌合类似物包括SSTR-2激动剂和多巴胺受体激动剂;或其药学上可接受的盐。在一种优选实施方式中,该嵌合类似物进一步包括SSTR-5激动剂或其药学上可接受的盐。
[0179]在本发明以上公开的这一方面的第三种相关实施方式中,该嵌合类似物包括SSTR-3激动剂和多巴胺受体激动剂;或其药学上可接受的盐。
[0180]在本发明以上公开的这一方面的第四种相关实施方式中,该嵌合类似物包括SSTR-5激动剂和多巴胺受体激动剂;或其药学上可接受的盐。
[0181]本发明的第八方面公开了一种对需要的患者所患有的肢端肥大症进行治疗的方法,其中所述的方法包括以治疗有效量的嵌合类似物向所述的患者给药,其中所述的嵌合类似物包括式(I),(II),(III),(IV),(V),(VI)(VII),(VIII),(IX)或(X)的化合物;表1所列的任何化合物;
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Ac-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Ac-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],
Dop2-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],或
Dop2-DTyr-DTyr-Caeg-环[DCys-3Pal-DTrp-Lys-Dcys]-Thr(Bzl)-Tyr-NH2;或
其药学上可接受的盐;或中间体化合物(3),(6),(11),(14),(18),(21),(24)或(27);或其有机盐或无机盐;以及治疗有效量是指有效地治疗所述患者所患的肢端肥大症的用量。在本发明这一方面的一种优选实施方式中,该嵌合类似物包括SSTR-5激动剂和多巴胺受体激动剂。更优选地,该嵌合类似物进一步包括SSTR-2激动剂。
[0182]在这一方面的另一优选方式中,所述患者已经患有肢端肥大症或具有患肢端肥大症的风险。
[0183]本发明的第九方面公开了对需要的患者所患的催乳素血症进行治疗的方法,其中所述的方法包括以治疗有效量的嵌合类似物向所述患者给药,其中所述的嵌合类似物包括式(I),(II),(III),(IV),(V),(VI)(VII),(VIII),(IX)或(X)的化合物;表1所列的任何化合物;
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Ac-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Ac-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTr-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],
Dop2-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],或
Dop2-DTyr-DTyr-Caeg-环[DCys-3Pal-DTrp-Lys-Dcys]-Thr(Bzl)-Tyr-NH2;或其药学上可接受的盐;或中间体化合物(3),(6),(11),(14),(18),(21),(24)或(27);或其有机盐或无机盐;以及治疗有效量是有效地治疗所述患者所患的催乳素血症的用量。在本发明这一方面的一种优选实施方式中,该嵌合类似物包括SSTR-5激动剂和多巴胺受体激动剂。更优选地,该嵌合类似物进一步包括SSTR-2激动剂。
[0184]在这一方面的另一优选方式中,患者已经患有催乳素血症或具有患催乳素血症的风险。
[0185]在一些实施方式中,本发明的化合物可包括DopA-Lys(DopA)这-结构,其中Lys是L-lysine,但用DLys表示的除外。A是1-13,例如Dop1,Dop2,Dop3,Dop4,Dop5,Dop6,Dop7,Dop8,Dop9,Dop10,Dop11,Dop12,以及Dop13。其中A为2(即Dop2-Lys(Dop2)),以及其中A为5(即Dop5-Lys(Dop5))的结构DopA-Lys(DopA)如下所示。
[0186]“Dop1”是指具有以下结构的化合物:
[0187]“Dop2”是指具有以下结构的化合物:
[0188]“Dop3”是指具有以下结构的化合物:
[0189]“Dop4”是指具有以下结构的化合物:
[0190]“Dop5”是指具有以下结构的化合物:
[0191]“Dop6”是指具有以下结构的化合物:
[0192]“Dop7”是指具有以下结构的化合物:
[0193]“Dop8”是指具有以下结构的化合物:
[0194]“Dop9”是指具有以下结构的化合物:
[0195]“Dop10”是指具有以下结构的化合物:
[0196]“Dop11”是指具有以下结构的化合物:
[0197]“Dop12”是指具有以下结构的化合物:
[0198]“Dop13”是指具有以下结构的化合物:
[0199]Lys(Dop2)的结构为:
[0200]Dop2-Lys(Dop2)的结构为:
[0201]Lys(Dop5)的结构为:
[0202]Dop5-Lys(Dop5)的结构为:
[0203]″烷基″是指含有一个或多个碳原子的烃基,当存在多个碳时,各个碳之间以单键连接。烷烃基可以是直链,或者含有一个或多个支链或环状基团。
[0204]″取代的烷基″是指烃基上的一个或多个氢原子被一个或多个取代基所取代的烷基,所述的取代基选自卤素(即氟、氯、溴和碘),-OH,-CN,-SH,-NH2,-NHCH3,-NO2,被1-5个卤素取代的-C1-2烷基,-CF3,-OCH3,-OCF3,以及-(CH2)0-4-COOH。在不同的实施方式中存在1,2,3或4个取代基。-(CH2)0-4-COOH的存在导致获得了烷基酸。含有-(CH2)0-4-COOH或由-(CH2)0-4-COOH构成的烷基酸包括2-降莰烷乙酸,叔丁酸和3-环戊基丙酸。
[0205]″杂烷基″是指烃基中的一个或多个碳原子被一个或多个以下基团替代的烷基:氨基,酰胺基,-O-或羰基。在不同的实施方式中存在1或2个杂原子。
[0206]″取代的杂烷基″是指烃基中一个或多个氢原子被一个或多个取代基取代的杂烷基,所述的取代基选自卤素(即氟、氯、溴和碘),-OH,-CN,-SH,-NH2,-NHCH3,-NO2,被1-5个卤素取代的-C1-2烷基,-CF3,-OCH3,-OCF3,以及-(CH2)0-4-COOH。在不同的实施方式中存在1,2,3或4个取代基。
[0207]″烯基″是指由两个或两个以上碳原子构成,且存在一个或多个碳-碳双键的烃基。烯烃基可为直链,或含有一个或多个支链或环状基团。
[0208]“取代的烯基”是指一个或多个氢原子被一个或多个取代基所取代的烯基,所述的取代基选自卤素(即氟、氯、溴和碘),-OH,-CN,-SH,-NH2,-NHCH3,-NO2,被1-5个卤素取代的-C1-2烷基,-CF3,-OCH3,-OCF3,以及-(CH2)0-4-COOH。在不同的实施方式中存在1,2,3或4个取代基。
[0209]“炔基”是指由两个或两个以上碳原子构成,且存在一个或多个碳-碳叁键的烃基。烯烃基可为直链,或含有一个或多个支链或环状基团。
[0210]″取代的炔基″是指一个或多个氢原子被一个或多个取代基所取代的炔基,所述的取代基选自卤素(即氟、氯、溴和碘),-OH,-CN,-SH,-NH2,-NHCH3,-NO2,被1-5个卤素取代的-C1-2烷基,-CF3,-OCH3,-OCF3,以及-(CH2)0-4-COOH。在不同的实施方式中存在1,2,3或4个取代基。
[0211]″芳基″是指至少一个环具有共轭π电子体系,含有至多两个共轭的或稠合环体系的任选取代的芳香基团。芳基包括碳环芳基,杂环芳基和联芳基基团。优选地,芳基是5或6元环。杂环芳基的优选原子是一个或多个硫,氧,和/或氮。芳基的例子包括苯基,1-萘基,2-萘基,吲哚,喹啉,2-咪唑,以及9-蒽。芳基取代基选自-C1-4烷基,-C1-4烷氧基,卤素(即氟、氯、溴和碘),-OH,-CN,-SH,-NH2,-NO2,被1-5个卤素取代的-C1-2烷基,-CF3,-OCF3,以及-(CH2)0-4-COOH。在不同的实施方式中存在0,1,2,3或4个取代基。
[0212]“酰基”是指X’-R”-C(O)-,其中R”是烷基,取代的烷基,杂烷基,取代的杂烷基,烯基,取代的烯基,炔基,取代的炔基,芳基,烷基芳基或取代的烷基芳基,以及X’为H或不存在。
[0213]″芳基烷基″或“烷基芳基”是指与″芳基″连接的″烷基″。
[0214]“Abu”是指α-氨基丁酸。
[0215]“Aepa”是指下列结构表示的4-(2-氨基乙基)-1-羧基甲基-哌嗪:
[0216]“Aib”是指α-氨基异丁基酸。
[0217]“Ala”或A”是指丙氨酸。
[0218]“β-Ala”是指β-丙氨酸。
[0219]“Arg”或“R”是指精氨酸。
[0220]“Asn”或“N”是指天门冬酰胺。
[0221]“Asp或“D”是指天冬氨酸。
[0222]“Caeg”是指下列结构表示的N-(2-氨基乙基)-N-(2-胞嘧啶基-1-氧代-乙基)-甘氨酸:
[0223]“Cys”或“C”是指半胱氨酸。
[0224]“Dab”是指2,4-二氨基丁酸。
0[0225]“Doc”是指下列结构表示的8-氨基-3,6-二氧杂辛酸:
[0226]“Gln”或“Q”是指谷酰胺。
[0227]“Glu”或“E”是指谷氨酸。
[0228]“Gly”或“G”是指甘氨酸。
[0229]“His”或“H”是指组氨酸。
[0230]“Ile”或“I”是指异亮氨酸。
[0231]“Leu”或“L”是指亮氨酸。
[0232]“Lys”或K”是指赖氨酸。
[0233]“Met”或“M”是指蛋氨酸。
[0234]“1Nal”是指β-(1-萘基)丙氨酸。
[0235]“2Nal”是指β-(2-萘基)丙氨酸。
[0236]“Nle”是指正亮氨酸。
[0237]“Orn”是指鸟氨酸。
[0238]“2Pal”是指β-(2-吡啶基)丙氨酸。
[0239]“3Pal”是指β-(3-吡啶基)丙氨酸。
[0240]“4Pal”是指β-(4-吡啶基)丙氨酸。
[0241]“Phe”或“F”是指苯基丙氨酸。
[0242]“Pro”或“P”是指脯氨酸。
[0243]“Ser”或“S”是指丝氨酸。
[0244]“Thr”或“T”是指苏氨酸。
[0245]“Thr-ol”是指下列结构表示的苏氨醇:
[0246]“Val”或“V”是指缬氨酸。
[0247]“(N-Me)Trp””是指N-α-甲基-色氨酸。
[0248]本文中采用的另一些缩写的定义如下:
[0249]“Ac”是指乙酰基。
[0250]“Boc”是指叔-丁氧基羰基。
[0251]“Bzl”是指苄基。
[0252]“DCM”是指二氯甲烷。
[0253]“DIC”是指N,N-二异丙基碳二亚胺。
[0254]“DIEA”是指二异丙基乙胺。
[0255]“Dmab”是指4-{N-(1-(4,4-二甲基-2,6-二氧杂环己烯)-3-甲基丁基)-氨基}苄基。
[0256]“DMAP”是指4-(二甲基氨基)吡啶。
[0257]“DMF”是指二甲基甲酰胺。
[0258]“DNP”是指2,4-二硝基苯基。
[0259]“Fmoc”是指芴基甲氧基羰基。
[0260]“HBTU”是指六氟磷酸2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基鎓盐。
[0261]“cHex”是指环己基。
[0262]“HOAT”是指六氟磷酸O-(7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基鎓盐。
[0263]“HOBt”是指1-羟基-苯并三唑。
[0264]“Mmt”是指4-甲氧基三苯甲游基。
[0265]“NMP”是指N-甲基吡咯烷酮。
[0266]“Pbf”是指2,2,4,6,7-五甲基二氢苯并呋喃-5-磺酰基。
[0267]“tBu”是指叔-丁基。
[0268]“TIS”是指三异丙基硅烷。
[0269]“TOS”是指甲苯磺酰基。
[0270]“trt”是指三苯甲游基。
[0271]“TFA”是指三氟乙酸。
[0272]“TFFH”是指四甲基氟代脲六氟磷酸盐。
[0273]“生长激素释放抑制因子受体激动剂”是指对生长激素释放抑制因子受体具有高结合亲和性(如Ki小于100nM,或优选小于10nM或更优选小于1nM)(结合亲和性采用下述的受体结合试验来定义)的化合物,例如受体可以是任何的不同亚型:如SSTR-1、SSTR-2、SSTR-3、SSTR-4以及SSTR-5,并且化合物能引起类似生长激素释放抑制因子的作用,如抑制cAMP在胞内的产生。
[0274]“生长激素释放抑制因子选择性激动剂”是指对一种生长激素释放抑制因子受体激动剂,它对某种生长激素释放抑制因子受体亚型的结合亲和性高于对任何其它生长激素释放抑制因子受体亚型的结合亲和性(如具有更低的Ki值),例如生长激素释放抑制因子SSTR-2选择性激动剂。
[0275]“多巴胺受体激动剂”是指对多巴胺受体具有高结合亲和性(如Ki小于100nM或优选小于10nM或更优选小于1nM)的化合物(结合亲和性采用下述的受体结合试验来定义),生长激素释放抑制因子受体例如为任何不同的亚型:如D1,D2,D3,D4,以及D5受体。
发明详述
[0276]本发明公开了生长激素释放抑制因子-多巴胺嵌合类似物,以及涉及治疗瘤形成、肢端肥大症和其他病症的治疗方法。
[0277]已经分离出各种生长激素释放抑制因子受体(SSTR′s)(如,SSTR-1,SSTR-2,SSTR-3,SSTR-4,以及SSTR-5)。生长激素释放抑制因子激动剂是与至少一种SSTR相结合的化合物(如,SSTR-1激动剂,SSTR-2激动剂,SSTR-3激动剂,SSTR-4激动剂或SSTR-5激动剂)。
[0278]生长激素释放抑制因子激动剂的另一些例子是下列的公开出版物中的通式所覆盖的或具体列举出的化合物,将这些公开出版物全文引入本文作为参考。
PCT申请No.WO 03/057214(2003)
U.S.申请No.20030191134(2003)
U.S.申请No.20030083241(2003)
PCT申请No.0210215(2002)
U.S.专利No.6,316,414(2001)
PCT申请No.WO 99/22735(1999)
PCT申请No.WO 98/08100(1998)
PCT申请No.WO 98/44921(1998)
PCT申请No.WO 98/45285(1998)
PCT申请No.WO 98/44922(1998)
EP申请No.P5164EU(发明人:G.Keri);
Van Binst,G.等.肽Research 5:8(1992);
Horvath,A.等.Abstract,″Conformations of Somatostatin AnalogsHaVing Antitumor ActiVity″,22nd European peptide Symposium,1992年9月13-19日,Interlaken,Switzerland;
PCT申请No.WO 91/09056(1991);
EP申请No.0363589A2(1990);
U.S.专利No.4,904,642(1990);
U.S.专利No.4,871,717(1989);
U.S.专利No.4,853,371(1989);
U.S.专利No.4,725,577(1988);
U.S.专利No.4,684,620(1987);
U.S.专利No.4,650,787(1987);
U.S.专利No.4,603,120(1986);
U.S.专利No.4,585,755(1986);
EP申请No.0 203 031 A2(1986);
U.S.专利No.4,522,813(1985);
U.S.专利No.4,486,415(1984);
U.S.专利No.4,485,101(1984);
U.S.专利No.4,435,385(1984);
U.S.专利No.4,395,403(1983);
U.S.专利No.4,369,179(1983);
U.S.专利No.4,360,516(1982);
U.S.专利No.4,358,439(1982);
U.S.专利No.4,328,214(1982);
U.S.专利No.4,316,890(1982);
U.S.专利No.4,310,518(1982);
U.S.专利No.4,291,022(1981);
U.S.专利No.4,238,481(1980);
U.S.专利No.4,235,886(1980);
U.S.专利No.4,224,199(1980);
U.S.专利No.4,211,693(1980);
U.S.专利No.4,190,648(1980);
U.S.专利No.4,146,612(1979);
U.S.专利No.4,133,782(1979);
U.S.专利No.5,506,339(1996);
U.S.专利No.4,261,885(1981);
U.S.专利No.4,728,638(1988);
U.S.专利No.4,282,143(1981);
U.S.专利No.4,215,039(1980);
U.S.专利No.4,209,426(1980);
U.S.专利No.4,190,575(1980);
EP专利No.0 389 180(1990);
EP申请No.0 505 680(1982);
EP申请No.0 083 305(1982);
EP申请No.0 030 920(1980);
PCT申请No.WO 88/05052(1988);
PCT申请No.WO 90/12811(1990);
PCT申请No.WO 97/01579(1997);
PCT申请No.WO 91/18016(1991);
U.K.申请No.GB 2,095,261(1981);以及
法国申请No.FR 2,522,655(1983)。
[0279]注意:对于本文所述的所有生长激素释放抑制因子激动剂,每一个氨基酸残基表示结构-NH-C(R)H-CO-,其中R是侧链(如Ala中为CH3)。氨基酸残基之间的短线表示连接氨基酸的肽键。此外,在氨基酸残基具有光学活性时,除非明确地指出为D-型,否则氨基酸残基都为L-型构型。为了清楚的缘故,Cys残基的两个自由硫醇之间存在的二硫键(二硫桥)就没有表示。普通氨基酸的缩写是根据IUPAC-IUB建议进行的。
生长激素释放抑制因子激动剂的合成
[0280]合成肽生长激素释放抑制因子激动剂的方法在文献中有充分记载,并且也是本领域技术人员力所能及的。例如,采用Fmoc化学的标准固相法在Rink酰胺MBHA树脂(4-(2’4’-二甲氧基苯基-Fmoc-氨基甲基)-苯氧基乙酰胺基-正亮氨酰基-MBHA树脂)上合成肽。然后用含有多巴胺部分的相应化合物处理在N-末端上带有自由氨基官能团的肽-树脂。采用TFA水/三异丙基硅烷(TIS)混合物从树脂中分离出最终产物。
[0281]例如,可按照欧洲专利申请0 395 417 A1中实施例I所述的方法合成H-D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2。带有取代的N-末端的生长激素释放抑制因子激动剂的合成例如可按照PCT公开文献No.WO88/02756,PCT公开文献No.WO 94/04752,和/或欧洲专利申请No.0 329 295中所述的方法完成。
[0282]可采用碘的MeOH/水溶液对肽进行环化,并采用乙腈-0.1%TFA/水-0.1%TFA缓冲液在C18反相制备HPLC上纯化。采用分析性HPLC和质谱测定均匀性,结果是每种肽的均匀性>95%。
[0283]一些异常的氨基酸购自下列商家:Fmoc-Doc-OH和Fmoc-AEPA-OH购自Chem-Impex International,Inc.(Wood Dale,IL,USA)。Fmoc-Caeg(Bhoc)-OH购自PerSeptive Biosystems(Framingham,MA,USA)。Bhoc表示二苯甲氧基羰基。
多巴胺激动剂的合成
[0284]合成多巴胺激动剂的方法也在文献中有充分记载,并且也是本领域技术人员所力所能及的。以下的反应路线和实施例中提供了进一步的合成方法。
反应路线1
反应路线2
反应路线3:
反应路线4:
反应路线5:
反应路线6:
反应路线7:
反应路线8:
反应路线9:
反应路线10:
反应路线11:
反应路线12:
反应路线13:
反应路线14:
反应路线15:
反应路线I
化合物6’,7’和8’可采用上述合成路线合成:
反应路线II
其中R”和R_独立地为H或C1-C4烷基
反应路线III
反应路线IV:
反应路线V:
反应路线VI:
生长激素释放抑制因子-多巴胺嵌合体的合成
[0285]可按照下述的反应路线和实施例合成生长激素释放抑制因子-多巴胺嵌合体。用于合成这些化合物的原料和中间体可以商购或可采用标准方法进行合成,标准方法的例子可参见Pharmazie 39,537(1984);collect Czech.Chem.Commun.33,577(1966);Helv.Chim.Acta 32,1947,(1949);U.S.P.5,097,031;USP 3,901,894;EP 0003667;和USP 4,526,892。合成肽的方法是本领域技术人员公知的(如,参见Stewart等,Solid Phase Synthesis,PierceChemical,2ndEd.1984;G.A.Grant;Synthetic肽;WH.,Freenand Co.,New York,1992;M.Bodenszky A.Bodanszky,The Practice of肽Synthesis,Spring Venlag.N.Y.1984)。
[0286]对生长激素和催乳激素分泌起到抑制作用的其它生长激素释放抑制因子-多巴胺嵌合体可用于治疗肢端肥大症在Saveanu等(J.Clin.Endocrin.和Metab.87:5545-5552,2002)的文献中有所公开,将该文献并入本文作为参考。
[0287]以下通过实施例对本发明展开阐述。这些实施例并不以任何方式限制本发明。
实施例1:Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
[0288]利用芴基甲氧基羰基(Fmoc)化学在ACT 396肽合成器(Advanced ChemTech,Louisville,KY)上自动合成Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2肽。采用取代度为0.66mmol/g的RINK AMIDE 4-甲基二苯甲胺(MBHA)树脂(Novabiochem.,San Diego,CA)(sub:0.66mmol/g,76mg,50μmol规模)。所采用的Fmoc氨基酸是购自NOVABIOCHEM(San Diego,CA)的Fmoc-DTrp(Boc)-OH,Fmoc-Lys(Boc)-OH,Fmoc-Thr(But)-OH,Fmoc-DPhe-OH,Fmoc-Cys(Trt)-OH,以及Fmoc-DLys(Dde))-OH,还有购自CHEM-IMPEX INTERNATIONAL,Inc.(Wood Dale,IL)的Fmoc-3ITyr-OH。合成的规模是50μmol。在每一反应周期中,ACT 396肽合成器所编程执行的步骤是:(1)用N-甲基吡咯烷酮(NMP)洗涤两次;(2)用溶于NMP中的20%吡啶脱去Fmoc保护基团,反应时间为1×5min和1×25min;(3)用NMP洗涤两次;和(4)用溶于N,N-二甲基甲酰胺(DMF)中4倍过量的Fmoc保护的氨基酸(0.20mmol),HOBt(0.2mmol),和N,N’-而乙丙基碳二亚胺(DIC)(0.2mmol)进行二次偶联,每次偶联的时间为1小时。树脂按照顺序依次进行偶联。
[0289]在肽链完成装配之后,脱去Fmoc基团,并采用NMP和二氯甲烷(DCM)彻底洗涤树脂。将树脂转移到置于摇床上的反应容器中,用溶于DMF中的2%肼进行2×30分钟的处理,以除去DLys侧链上Dde保护的基团。依次用DMF,MeOH和DCM洗涤之后,使树脂与Dop2-OH(54mg,3.0eq),六氟磷酸溴-三-吡咯烷-膦鎓盐(PyBrop,82mg,3.4eq),1-羟基-7-氮杂苯并三唑(HOAT,0.4mg,3.0eq),五氟苯酚(18.4mg,4eq),DMAP(0.25mL溶于DMF中浓度为0.1M的溶液,1.0eq)和二异丙基乙基胺(DIEA)(53μL,4eq)一起振荡过夜。
[0290]依次采用DMF,MeOH和DCM洗涤之后,再采用TFA(4.75mL),H2O(0.4mL)和三异丙基硅烷(TIS,0.425mL)的混合物对树脂进行2小时处理。通过过滤除去树脂。将滤液倾倒到70mL乙醚中。滤出形成的沉淀并用乙醚彻底洗涤。将粗产物溶解于5mL乙酸水溶液中(水/乙酸=1∶1)。用50H2O和20mL乙腈稀释溶液,向该溶液中滴加碘的甲醇溶液,直到溶液保持为黄色。缓慢搅拌溶液1小时,然后加入Na2S2O3水溶液终止反应。在采用C18DYNAMAX-100A°(4×43cm,Varian,Walnut Creek,CA)柱的反相制备性HPLC上提纯粗产物。采用在1小时内从90%A+10%B变化到60%A+40%B的线性梯度对柱进行洗脱,其中A是含0.1%TFA的水溶液,B是含0.1%TFA的乙腈溶液。通过紫外线(UV)吸收收集含有主要成分的级分,进行冻干。分析性HPLC分析得到的纯度为95.7%。电子轰击离子质谱(ESI质谱)分析得到的分子量为1982.6(与计算分子量1983.3相一致)。
实施例2:Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2
[0291]Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2这一化合物的合成基本按照实施例所述的Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2的方法合成,但作如下改变。在完成肽链装配之后,将树脂转移到置于摇床上的反应容器中,采用含25%哌啶的DMF溶液进行30分钟的处理,脱去N-末端的Fmoc保护基。依次用DMF,MeOH和DCM洗涤之后,树脂与Dop2-OH(3.0eq),PyBrop(3.4eq),HOAT(3.0eq),DMAP(1.0eq)和DIEA(4eq)一起振荡过夜。进行分离和提纯之后,发现预期的产品的纯度为95%(分析性HPLC分析的结果)。ESI质谱分析的结果是分子量为2145.9(与计算分子量2145.6相一致)。
实施例3:Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
[0292]标题化合物的合成基本按照上述实施例2所述合成Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2的方法进行,但采用Fmoc-Lys(Fmoc)-OH在最终的Lys残基的N-末端进行偶联。产物是均匀的,纯度为93.9%(HPLC)。ESI质谱分析的结果是分子量为2020.9(与计算分子量2020.1相一致)。
实施例4:Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
[0293]标题化合物的合成基本按照上述实施例1所述合成Dop2-DPhe-Doc-DPhe-c[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2的方法进行。最终产品的纯度为93.9%(分析性HPLC分析的结果)。ESI质谱分析表明分子量为1514.50(与计算分子量1514.63相一致)。
实施例5:中间体化合物(3)的合成
[0294]将R(-)降阿朴吗啡化合物
1(购自Sigma,200mg,0.79mmol)和对-甲苯磺酸一水合物(451mg,2.37mmol)在丙酮(20mL)中室温搅拌过夜。减压除去溶剂。将残余物溶解于二氯甲烷(30mL)中,用饱和NaHCO3水溶液(2次)和盐水(2次)洗涤,采用无水MgSO4干燥,过滤,并在真空中进行浓缩。用二氧化硅柱色谱提纯残余物,得到丙酮化合物-R(-)降阿朴吗啡,得到化合物
2。
[0295]在0℃下,向化合物
2(167mg,0.57mmol)和N,N-二异丙基乙基胺(219mg,1.7mmol)溶于二氯甲烷(20mL)的混合物中滴加溴化乙酸(236mg,1.7mmol)。然后将混合物升温到室温,搅拌6小时。用盐水洗涤溶液两次,干燥(无水MgSO4),过滤,并在真空下浓缩。采用二氧化硅柱色谱提纯残余物,得到中间体化合物
3。
实施例6:中间体化合物(6)的合成
[0296]将R(-)降阿朴吗啡
4(200mg,0.748mmol),2-甲基丙烯(83.9mg,1.50mmol),和催化量的浓H2SO4在CH2Cl2(20mL)中的混合物在室温下搅拌过夜。用饱和NaHCO3水溶液(2次)和盐水(2次)洗涤溶液,干燥(无水MgSO4),过滤,并在真空下浓缩。采用二氧化硅柱色谱提纯残余物,得到化合物
5。
[0297]在0℃下,向化合物
5(150mg,0.486mmol)和N,N-二异丙基乙基胺(188mg,1.46mmol)溶于二氯甲烷(20mL)的混合物中滴加溴乙酸(203mg,1.46mmol)。然后使混合物升温到室温并搅拌6小时。用盐水洗涤溶液2次,干燥(无水MgSO4),过滤,并在真空下浓缩。用二氧化硅柱色谱提纯残余物,得到中间体化合物
6。
实施例7:中间体化合物(11)的合成
[0298]向吲哚酮
10(WO 9415918,218mg,1.00mmol)和N,N-二异丙基乙基胺(258mg,2.0mmol)溶于二氯甲烷(20mL)的混合物中加入4-碘丁酸(214mg,1.0mmol)。得到的溶液在室温下搅拌过夜。溶液在真空下浓缩。用二氧化硅柱色谱提纯残余物,得到中间体化合物
11。
实施例8:中间体化合物(14)的合成
[0299]向1-金刚烷基胺盐酸盐
12(Aldrich,187mg,1.00mmol)和N,N-二异丙基乙基胺(387mg,3.0mmol)溶于二氯甲烷(20mL)的混合物中加入4-碘丁酸(214mg,1.0mmol)。得到的溶液在室温下搅拌过夜。溶液用盐水洗涤2次,干燥(无水MgSO4),过滤,并在真空下浓缩。用二氧化硅柱色谱提纯残余物,得到化合物
13。
[0300]在0℃下,向溶于二噁烷(6mL)和水(3mL)的化合物
13(190mg,0.8mmol)的溶液中加入1N NaOH(1.0mL)。在30分钟的时间内向得到的溶液中加入二碳酸二-叔-丁基酯(192mg,0.88mmol)。混合物在室温下搅拌12小时。减压除去二噁烷。向得到的水溶液中加入乙酸乙酯。在0℃下加入0.2N HCl,将溶液的pH调节到约pH3。分离出有机层,用水洗涤两次,用无水MgSO4干燥,过滤,并在真空下浓缩。用二氧化硅柱色谱提纯残余物,得到中间体化合物
14。
实施例9:中间体化合物(18)的合成
[0301]将非诺多泮(fenoldopam)
15(购自Sigma,306mg,1.00mmol)和对-甲苯磺酸-水合物(476mg,2.50mmol)溶于丙酮(30mL)的混合物在室温下搅拌过夜。减压除去溶剂。将残余物溶解于二氯甲烷(30mL)中,然后用饱和NaHCO3水溶液(2次)和盐水(2times),干燥无水MgSO4,过滤,并在真空下浓缩。用二氧化硅柱色谱纯化残余物,得到丙酮化物-非诺多泮
16。
[0302]丙酮化物-非诺多泮
16(277mg,0.80mmol),2-甲基丙烯(67.0mg,1.20mmol),以及催化量的浓H2SO4溶于CH2Cl2(20mL)的混合物在室温下搅拌过夜。用饱和NaHCO3水溶液(2次)和盐水(2次)洗涤溶液,用无水MgSO4干燥,过滤,并在真空下浓缩。用二氧化硅柱色谱纯化残余物,得到化合物
17。
[0303]向化合物
17(201mg,0.50mmol)和N,N-二异丙基乙基胺(129mg,1.0mmol)溶于二氯甲烷(20mL)的混合物中加入4-碘丁酸(107mg,0.5mmol)。得到的溶液在室温下搅拌过夜。溶液用盐水洗涤2次,用无水MgSO4干燥,过滤,并在真空下浓缩。用二氧化硅柱色谱纯化残余物,得到中间体化合物
18。
实施例10:中间体化合物(21)的合成
[0304]向溶于二噁烷(20mL)和水(10mL)的化合物
19(169mg,1.0mmol)溶液中加入4-碘丁酸(214mg,1.0mmol)。使得到的溶液搅拌24小时。在此期间,加入0.5N NaOH溶液保持溶液的pH为7-8。减压除去溶剂。用二氧化硅柱色谱提纯残余物,得到化合物
20。
[0305]在0℃,向溶于二噁烷(6mL)和水(3mL)的化合物
20(179mg,0.7mmol)的溶液中加入1N NaOH(2.1mL)。在30分钟内向得到的溶液中加入二碳酸二-叔-丁基酯(336mg,1.54mmol)。混合物在室温下搅拌12小时。减压除去二噁烷。向得到的水溶液中加入乙酸乙酯。在0℃下加入0.2N HCl溶液调节溶液的pH为约pH3。分离出有机层,用水洗涤两次,用无水MgSO4干燥,过滤,并在真空下浓缩。用二氧化硅柱色谱提纯残余物,得到中间体化合物
21。
实施例11:中间体化合物(24)的合成
[0306]向溶于二噁烷(20mL)和水(10mL)的化合物
22(169mg,1.0mmol)的溶液中加入4-碘丁酸(214mg,1.0mmol)。使得到的溶液搅拌24小时。在此期间,加入0.5N NaOH溶液以保持溶液的pH为7-8。减压除去溶剂。采用二氧化硅柱色谱提纯残余物,得到化合物
23。
[0307]在0℃下,向溶于二噁烷(6mL)和水(3mL)的化合物
23(179mg,0.7mmol)的溶液中加入1NNaOH(1.4mL)。在30分钟内向得到的溶液中加入二碳酸二-叔-丁基酯(168mg,0.77mmol)。混合物在室温下搅拌12小时。在0℃下加入0.2N HCl溶液调节溶液的pH为约pH4-5。溶液在真空下浓缩。用二氧化硅柱色谱提纯残余物,得到中间体化合物
24。
实施例12:中间体化合物(27)的合成
[0308]化合物
25(205mg,1.00mmol),2-甲基丙烯(84mg,1.50mmol),以及浓H2SO4溶于CH2Cl2(20mL)的混合物在室温下搅拌过夜。用饱和NaHCO3水溶液(2次)和盐水(2次)洗涤溶液,用无水MgSO4干燥,过滤,并在真空下浓缩。用二氧化硅柱色谱提纯残余物,得到化合物
26。
[0309]向1-金刚烷基胺盐酸盐
26(209mg,0.8mmol)和N,N-二异丙基乙基胺(310mg,2.4mmol)溶于二氯甲烷(20mL)的混合物中加入4-碘丁酸(171mg,0.8mmol)。得到的溶液在室温下搅拌过夜。溶液在在真空下浓缩。用二氧化硅柱色谱提纯残余物,得到中间体化合物
27。
其它化合物的合成
[0310]可按照上述的方法合成下列化合物。
[0311]为将Dop1,Dop2,Dop3或Dop4残基引入到肽中,在合成中分别采用Dop1-OH,Dop2-OH,Dop3-OH或Dop4-OH(WO 02/100888A1)。
[0312]为合成含有Dop5的肽,采用Fmoc-Dopa(丙酮化物)-OH(Novabiochem,San Diego,CA)。
[0313]为合成含有Dop6残基的肽,在合成中采用化合物
11。
[0314]为合成含有Dop7残余物的肽,在合成中采用.化合物
21。
[0315]为合成含有Dop8残余物的肽,在合成中采用化合物
14。
[0316]为合成含有Dop9残余物的肽,在合成中采用化合物
24。
[0317]为合成含有Dop10残余物的肽,在合成中采用化合物
3。
[0318]为合成含有Dop11残余物的肽,在合成中采用化合物
6。
[0319]为合成含有Dop12残余物的肽,在合成中采用化合物
27。
[0320]为合成含有Dop13残余物的肽,在合成中采用化合物
18。
[0321]表1列出了可能具有体外或体内生长激素释放抑制因子和多巴胺活性的生长激素释放抑制因子-多巴胺嵌合类似物。
表1
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Ac-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Ac-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop2-Lys(Ac)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-DLys(Ac)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop3-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop4-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop3-Aepa-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop4-Aepa-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop5-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop6-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop7-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop8-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop9-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop10-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop11-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop12-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop13-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop5-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop6-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop7-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop8-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop9-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop10-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop11-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop12-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop13-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop5-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop6-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop7-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop8-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop9-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop10-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop11-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop12-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop13-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop5-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop6-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop7-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop8-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop9-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop10-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop11-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop12-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop13-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop5-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop6-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop7-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop8-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop9-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop10-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop11-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-o1
Dop12-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop13-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop5-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop6-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop7-环[Cys-Phe-DT-Lys-Thr-Cys]-Thr-ol
Dop8-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop9-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop10-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop11-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop12-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop13-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop5-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop6-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop7-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop8-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop9-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop10-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop11-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop12-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop13-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop5-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop6-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop7-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop8-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop9-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop10-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop11-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop12-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop13-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop1-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop1-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop2-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop3-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop4-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop3-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop4-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop5-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop6-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop7-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop8-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop9-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop10-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop11-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop12-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop13-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop3-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop4-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop5-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop6-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop7-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop8-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop9-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop10-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop11-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop12-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop13-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop1-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop2-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop3-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop4-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop1-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop2-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop3-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop4-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop5-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop6-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop7-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop8-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop9-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop10-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop11-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop12-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop13-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop1-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop2-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop3-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop4-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop1-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop2-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop3-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop4-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop5-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop6-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop7-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop8-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop9-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop10-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop11-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop12-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop13-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-SerBzl)-Tyr-NH2
Dop5-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop6-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop7-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop8-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop9-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop10-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop11-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop12-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop13-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop5-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop6-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop7-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop8-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop9-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop10-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop11-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop12-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop13-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop5-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop6-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop7-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop8-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop9-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop10-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop11-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop12-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop13-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-DLys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-Lys(Dop2)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-DLys(Dop2)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-DLys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop1-Lys(Dop1)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop1-Lys(Dop1)-Aepa-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop1-Lys(Dop1)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop1-Lys(Dop1)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop1-Lys(Dop1)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop1-DLys(Dop1)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop1-DLys(Dop1)-Aepa-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop1-DLys(Dop1)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop1-DLys(Dop1)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop1-DLys(Dop1)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop1-Lys(Dop1)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop1-Lys(Dop1)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop1-Lys(Dop1)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop1-Lys(Dop1)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop1-Lys(Dop1)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop1-Lys(Dop1)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop1-Lys(Dop1)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop1-Lys(Dop1)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop1-Lys(Dop1)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop1-Lys(Dop1)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop1-Lys(Dop1)-Lys-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop1-Lys(Dop1)-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop1-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop1-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop1-Lys(Dop2)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop1-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-Lys(Dop2)-Aepa-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-Lys(Dop2)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-Lys(Dop2)-Aepa-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-DLys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-DLys(Dop2)-Aepa-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-DLys(Dop2)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-DLys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-DLys(Dop2)-Aepa-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-Lys(Dop2)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop2-Lys(Dop2)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop2-Lys(Dop2)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop2-Lys(Dop2)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop2-Lys(Dop2)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop2-Lys(Dop2)-Lys-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop2-Lys(Dop2)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop3-Lys(Dop3)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop3-Lys(Dop3)-Aepa-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop3-Lys(Dop3)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop3-Lys(Dop3)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop3-Lys(Dop3)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop3-DLys(Dop3)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop3-DLys(Dop3)-Aepa-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop3-DLys(Dop3)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop3-DLys(Dop3)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop3-DLys(Dop3)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop3-Lys(Dop3)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop3-Lys(Dop3)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop3-Lys(Dop3)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop3-Lys(Dop3)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop3-Lys(Dop3)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop3-Lys(Dop3)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop3-Lys(Dop3)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop3-Lys(Dop3)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop3-Lys(Dop3)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop3-Lys(Dop3)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop3-Lys(Dop3)-Lys-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop3-Lys(Dop3)-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop3-Lys(Dop3)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop3-Lys(Dop3)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop3-Lys(Dop3)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop3-Lys(Dop3)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop4-Lys(Dop4)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop4-Lys(Dop4)-Aepa-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop4-Lys(Dop4)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop4-Lys(Dop4)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop4-Lys(Dop4)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop4-DLys(Dop4)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop4-DLys(Dop4)-Aepa-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop4-DLys(Dop4)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop4-DLys(Dop4)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop4-DLys(Dop4)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop4-Lys(Dop4)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop4-Lys(Dop4)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop4-Lys(Dop4)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop4-Lys(Dop4)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop4-Lys(Dop4)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop4-Lys(Dop4)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop4-Lys(Dop4)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop4-Lys(Dop4)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop4-Lys(Dop4)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop4-Lys(Dop4)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop4-Lys(Dop4)-Lys-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop4-Lys(Dop4)-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop4-Lys(Dop4)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop4-Lys(Dop4)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop4-Lys(Dop4)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop4-Lys(Dop4)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop5-Lys(Dop5)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop5-Lys(Dop5)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop5-Lys(Dop5)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop5-DLys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop5-DLys(Dop5)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop5-DLys(Dop5)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop5-DLys(Dop5)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop5-Lys(Dop5)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop5-Lys(Dop5)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop5-Lys(Dop5)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop5-Lys(Dop5)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop5-Lys(Dop5)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop5-Lys(Dop5)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop5-Lys(Dop5)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop5-Lys(Dop5)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop5-Lys(Dop5)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop5-Lys(Dop5)-Lys-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop5-Lys(Dop5)-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop5-Lys(Dop5)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop5-Lys(Dop5)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop5-Lys(Dop5)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop6-Lys(Dop6)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop6-Lys(Dop6)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop6-Lys(Dop6)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop6-Lys(Dop6)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop6-DLys(Dop6)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop6-DLys(Dop6)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop6-DLys(Dop6)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop6-DLys(Dop6)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop6-Lys(Dop6)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop6-Lys(Dop6)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop6-Lys(Dop6)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop6-Lys(Dop6)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop6-Lys(Dop6)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop6-Lys(Dop6)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop6-Lys(Dop6)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop6-Lys(Dop6)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop6-Lys(Dop6)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop6-Lys(Dop6)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop6-Lys(Dop6)-Lys-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop6-Lys(Dop6)-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop6-Lys(Dop6)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop6-Lys(Dop6)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop6-Lys(Dop6)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop6-Lys(Dop6)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop7-Lys(Dop7)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop7-Lys(Dop7)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop7-DLys(Dop7)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop7-DLys(Dop7)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop7-Lys(Dop7)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop7-Lys(Dop7)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop7-Lys(Dop7)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop7-Lys(Dop7)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop7-Lys(Dop7)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop7-Lys(Dop7)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop7-Lys(Dop7)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop7-Lys(Dop7)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop8-Lys(Dop8)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop8-Lys(Dop8)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop8-DLys(Dop8)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop8-DLys(Dop8)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop8-Lys(Dop8)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop8-Lys(Dop8)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop8-Lys(Dop8)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop8-Lys(Dop8)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop8-Lys(Dop8)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop8-Lys(Dop8)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop8-Lys(Dop8)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop8-Lys(Dop8)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop9-Lys(Dop9)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop9-Lys(Dop9)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop9-DLys(Dop9)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop9-DLys(Dop9)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop9-Lys(Dop9)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop9-Lys(Dop9)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop9-Lys(Dop9)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop9-Lys(Dop9)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop9-Lys(Dop9)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop9-Lys(Dop9)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop9-Lys(Dop9)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop9-Lys(Dop9)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop10-Lys(Dop10)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop10-Lys(Dop10)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop10-DLys(Dop10)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop10-DLys(Dop10)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop10-Lys(Dop10)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop10-Lys(Dop10)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop10-Lys(Dop10)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop10-Lys(Dop10)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop10-Lys(Dop10)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop10-Lys(Dop10)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop10-Lys(Dop10)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop10-Lys(Dop10)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop11-Lys(Dop11)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop11-Lys(Dop11)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop11-DLys(Dop11)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop11-DLys(Dop11)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop11-Lys(Dop11)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop11-Lys(Dop11)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop11-Lys(Dop11)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop11-Lys(Dop11)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop11-Lys(Dop11)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop1l-Lys(Dop11)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop11-Lys(Dop11)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop11-Lys(Dop11)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop12-Lys(Dop12)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop12-Lys(Dop12)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop12-DLys(Dop12)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop12-DLys(Dop12)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop12-Lys(Dop12)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop12-Lys(Dop12)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop12-Lys(Dop12)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop12-Lys(Dop12)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop12-Lys(Dop12)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop12-Lys(Dop12)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop12-Lys(Dop12)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop12-Lys(Dop12)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop13-Lys(Dop13)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop13-Lys(Dop13)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop13-DLys(Dop10)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop13-DLys(Dop13)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop13-Lys(Dop13)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop13-Lys(Dop13)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop13-Lys(Dop13)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop13-Lys(Dop13)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2
Dop13-Lys(Dop13)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop13-Lys(Dop13)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol
Dop13-Lys(Dop13)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop13-Lys(Dop13)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2
Dop1-Lys(Dop1)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop1-Lys(Dop1)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop1-DLys(Dop1)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop1-DLys(Dop1)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop1-Lys(Dop1)-Lys-Caeg-环[DCys-3Pa1-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop1-Lys(Dop1)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop1-DLys(Dop1)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop1-DLys(Dop1)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dopl-Lys(Dop1)-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop1-Lys(Dop1)-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop1-DLys(Dop1)-Aepa-Caeg-环
[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop1-DLys(Dop1)-Aepa-Caeg-环
[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop1-Lys(Dop1)-Lys-Aepa-Caeg-环
[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop1-Lys(Dop1)-Lys-Aepa-Caeg-环
[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop1-DLys(Dop1)-Lys-Aepa-Caeg-环
[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop1-DLys(Dop1)-Lys-Aepa-Caeg-环
[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop2-Lys(Dop2)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop2-Lys(Dop2)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop2-DLys(Dop2)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop2-DLys(Dop2)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop2-Lys(Dop2)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop2-Lys(Dop2)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop2-DLys(Dop2)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop2-DLys(Dop2)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop2-Lys(Dop2)-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop2-Lys(Dop2)-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop2-DLys(Dop2)-Aepa-Caeg-环
[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop2-DLys(Dop2)-Aepa-Caeg-环
[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop2-Lys(Dop2)-Lys-Aepa-Caeg-环
[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop2-Lys(Dop2)-Lys-Aepa-Caeg-环
[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop2-DLys(Dop2)-Lys-Aepa-Caeg-环
[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop2-DLys(Dop2)-Lys-Aepa-Caeg-环
[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop3-Lys(Dop3)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop3-Lys(Dop3)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop3-Lys(Dop3)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop3-Lys(Dop3)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop3-Lys(Dop3)-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop3-Lys(Dop3)-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop3-DLys(Dop3)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop3-DLys(Dop3)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop3-DLys(Dop3)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop3-DLys(Dop3)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop3-DLys(Dop3)-Aepa-Caeg-环
[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop3-DLys(Dop3)-Aepa-Caeg-环
[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop4-Lys(Dop4)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop4-Lys(Dop4)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop4-Lys(Dop4)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop4-Lys(Dop4)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop4-Lys(Dop4)-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop4-Lys(Dop4)-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop4-Lys(Dop4)-Lys-Aepa-Caeg-环
[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop4-Lys(Dop4)-Lys-Aepa-Caeg-环
[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop4-DLys(Dop4)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop4-DLys(Dop4)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop4-DLys(Dop4)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop4-DLys(Dop4)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop4-DLys(Dop4)-Aepa-Caeg-环
[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop4-DLys(Dop4)-Aepa-Caeg-环
[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop4-DLys(Dop4)-Lys-Aepa-Caeg-环
[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop4-DLys(Dop4)-Lys-Aepa-Caeg-环
[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop5-Lys(Dop5)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop5-Lys(Dop5)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop5-DLys(Dop5)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop5-DLys(Dop5)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop5-Lys(Dop5)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop5-Lys(Dop5)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop5-DLys(Dop5)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop5-DLys(Dop5)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop6-Lys(Dop6)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop6-Lys(Dop6)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop6-DLys(Dop6)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop6-DLys(Dop6)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop6-Lys(Dop6)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop6-Lys(Dop6)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop6-DLys(Dop6)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop6-DLys(Dop6)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop7-Lys(Dop7)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop7-Lys(Dop7)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop7-Lys(Dop7)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop7-Lys(Dop7)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop8-Lys(Dop8)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop8-Lys(Dop8)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop8-Lys(Dop8)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop8-Lys(Dop8)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop9-Lys(Dop9)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop9-Lys(Dop9)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop9-Lys(Dop9)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop9-Lys(Dop9)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop10-Lys(Dop10)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop10-Lys(Dop10)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop10-Lys(Dop10)-Lys-Caeg-环
[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop10-Lys(Dop10)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop11-Lys(Dop11)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop11-Lys(Dop11)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop11-Lys(Dop11)-Lys-Caeg-环
[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop11-Lys(Dop11)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop12-Lys(Dop12)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop12-Lys(Dop12)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop12-Lys(Dop12)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop12-Lys(Dop12)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop13-Lys(Dop13)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop13-Lys(Dop13)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop13-Lys(Dop13)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop13-Lys(Dop13)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop1-Lys(Dop1)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop1-Lys(Dop1)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop1-DLys(Dop1)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop1-DLys(Dop1)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop1-Lys(Dop1)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop1-DLys(Dop1)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop2-Lys(Dop2)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop2-Lys(Dop2)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop2-DLys(Dop2)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop2-DLys(Dop2)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop2-Lys(Dop2)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop2-DLys(Dop2)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop3-Lys(Dop3)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop3-Lys(Dop3)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop3-Lys(Dop3)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop4-Lys(Dop4)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop4-Lys(Dop4)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop4-Lys(Dop4)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop5-Lys(Dop5)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop5-Lys(Dop5)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop5-DLys(Dop5)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop5-DLys(Dop5)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop5-Lys(Dop5)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop5-DLys(Dop5)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop6-Lys(Dop6)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop6-Lys(Dop6)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop6-DLys(Dop6)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop6-DLys(Dop6)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop6-Lys(Dop6)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop6-DLys(Dop6)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop7-Lys(Dop7)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop7-Lys(Dop7)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop7-Lys(Dop7)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop8-Lys(Dop8)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop8-Lys(Dop8)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop9-Lys(Dop9)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop9-Lys(Dop9)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop10-Lys(Dop10)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop10-Lys(Dop10)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop11-Lys(Dop11)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop11-Lys(Dop11)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop12-Lys(Dop12)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop12-Lys(Dop12)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop13-Lys(Dop13)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2
Dop13-Lys(Dop13)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2
Dop1-DPhe-环[Cys-3ITyr(Dop1)-DTrp-Lys-Val-Cys]-Thr-NH2
Dop1-DPhe-Doc-DPhe-环[Cys-3ITyr(Dop1)-DTrp-Lys-Val-Cys]-Thr-NH2
Dop1-DLys(Dop1)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop1-DLys(Dop1)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop1-Lys(Dop1)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop1-Lys(Dop1)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop1-Lys(Dop1)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop1-DLys(Dop1)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop1-Lys(Dop1)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop1-Lys(Dop1)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop1-DLys(Dop1)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop1-DLys(Dop1)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop1-DLys(Dop1)-DPhe-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop1-DLys(Dop1)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop1-Lys(Dop1)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop1-Lys(Dop1)-DPhe-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop1-Lys(Dop1)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop1-DLys(Dop1)-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop1-Lys(Dop1)-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop1-Lys(Dop1)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop1-DLys(Dop1)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop1-DLys(Dop1)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop1-DLys(Dop1)-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop1-DLys(Dop1)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop1-Lys(Dop1)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop1-Lys(Dop1)-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop1-Lys(Dop1)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop1-DLys(Dop1)-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop1-Lys(Dop1)-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop1-Lys(Dop1)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop1-DLys(Dop1)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop1-DLys(Dop1)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop2-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop2-Lys(Dop2)-Aepa-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop2-Lys(Dop2)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop2-DLys(Dop2)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop2-DLys(Dop2)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop2-Lys(Dop2)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop2-Lys(Dop2)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop2-DLys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop2-DLys(Dop2)-Aepa-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop2-DLys(Dop2)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-DLys(Dop2)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-Lys(Dop2)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-DLys(Dop2)-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-Lys(Dop2)-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-Lys(Dop2)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-DLys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-DLys(Dop2)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop2-DLys(Dop2)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop2-Lys(Dop2)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop2-DLys(Dop2)-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop2-Lys(Dop2)-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop2-Lys(Dop2)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop2-DLys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop2-DLys(Dop2)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop3-Lys(Dop3)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop4-Lys(Dop4)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop3-Lys(Dop3)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop4-Lys(Dop4)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop5-DLys(Dop5)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop5-Lys(Dop5)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop5-Lys(Dop5)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop5-DLys(Dop5)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop5-Lys(Dop5)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop5-Lys(Dop5)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop5-DLys(Dop5)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop5-DLys(Dop5)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop5-DLys(Dop5)-DPhe-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop5-Lys(Dop5)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop5-Lys(Dop5)-DPhe-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop5-DLys(Dop5)-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop5-Lys(Dop5)-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop5-Lys(Dop5)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop5-DLys(Dop5)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop5-DLys(Dop5)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2
Dop5-DLys(Dop5)-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop5-Lys(Dop5)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop5-Lys(Dop5)-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop5-DLys(Dop5)-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop5-Lys(Dop5)-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop5-Lys(Dop5)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop5-DLys(Dop5)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop5-DLys(Dop5)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop6-Lys(Dop6)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop7-Lys(Dop7)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop8-Lys(Dop8)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop9-Lys(Dop9)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop10-Lys(Dop10)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop11-Lys(Dop11)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop12-Lys(Dop12)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop13-Lys(Dop13)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop6-Lys(Dop6)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop7-Lys(Dop7)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop8-Lys(Dop8)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop9-Lys(Dop9)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop10-Lys(Dop10)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop11-Lys(Dop11)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop12-Lys(Dop12)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop13-Lys(Dop13)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
[0322]本发明的一些化合物具有至少一个不对称中心。分子中也可以有另外的不对称中心,这取决于分子上不同取代基的性质。每个这样的不对称中心产生两个旋光异构体,所有这些旋光异构体,如分离的、纯的或部分纯的旋光异构体、外消旋混合物或其非对映混合物均包括在本发明的范围内。
[0323]本发明的化合物通常可以其药学上可接受的酸加成盐的形式分离出来,如使用无机酸或有机酸得到的盐。所述酸的实例包括盐酸、硝酸、硫酸、磷酸、甲酸、乙酸、三氟乙酸、丙酸、马来酸、琥珀酸、D-酒石酸、L-酒石酸、丙二酸、甲磺酸等。另外,某些含有酸官能团如羧基的化合物可以其无机盐的形式分离出来,其中的对应的离子选自Na,K,Li,Ca,Mg等,也可从有机碱中分离出来。
[0324]所述药学上可接受的盐可通过下述方法得到:取约1当量的本发明的化合物,使其与约1当量或更多的所希望得到的相应盐的酸接触。合成方法和分离方法是本领域的技术人员所公知的。
[0325]本发明的化合物可以通过下列方式给药:口服、胃肠外(如肌内、腹膜内、静脉内或皮下注射或植入)、鼻腔给药、阴道、直肠、舌下、或局部给药,本发明的化合物可与药学上可接受的载体一起制成药剂以提供与各种给药途径相适应的剂型。因此,本发明公开了含有下列组分的药物组合物:作为活性组分的至少一种本发明的化合物,其与药学上可接受的载体相联合。
[0326]用于口服给药的固体剂型包括胶囊、片剂、丸剂、粉末剂和粒剂。在这些固体剂型中,活性化合物与至少一种惰性的药学上可接受的载体混合,如蔗糖、乳糖、或淀粉。这些剂型也可包括除惰性稀释剂以外的物质,如润滑剂(如硬酯酸镁)。胶囊、片剂和丸剂还可含有缓冲剂。片剂和丸剂还可包有肠溶衣。
[0327]用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆、酏剂,其中含有本领域常用的惰性稀释剂如水。除上述惰性稀释剂以外,组合物也可包括辅剂,如润湿剂、乳化剂、悬浮剂和甜味剂、调味剂和芳香剂。
[0328]本发明用于胃肠外给药的制剂包括无菌水溶液或非水溶液、悬浮液或乳液。非水溶剂或载体的实例包括丙二醇、聚乙二醇、植物油如橄榄油和玉米油,明胶和可注射的有机酯类如油酸酯。该剂型还可包括辅剂如防腐剂、润湿剂、乳化剂和分散剂。它们可通过下列方式灭菌:通过细菌保留过滤器(bacteria-retaining filter)进行过滤,在组合物中加入灭菌剂,照射组合物或加热组合物。在使用前,可以制成溶解在无菌水或一些其他无菌可注射介质中的无菌固体组合物的形式。
[0329]用于直肠或阴道给药的组合物优选是栓剂,除活性物质外,其可含有赋型剂如可可乳脂或栓剂蜡。
[0330]用于鼻腔或舌下给药的组合物也可采用本领域公知的标准赋型剂制备。
[0331]通常,本发明的组合物中活性组分的有效剂量可以不同,但活性组分的量必须是获得适宜剂型的量。选择的剂量取决于所希望达到的治疗效果、给药途径和治疗持续的时间,这些都是本领域的公知常识。通常,对人和其他动物如哺乳动物的给药剂量每天在0.0001-100mg/kg体重。
[0332]优选的剂量范围在每天0.01-10.0mg/kg体重,其可以是一次给药的剂量或分为多次给药的剂量。
生长激素释放抑制因子受体的特异性和选择性分析
[0333]通过对用每一种SSTR亚型稳定转染的CHO-K1细胞进行放射性配体结合分析,测定用于合成生长激素释放抑制因子-多巴胺嵌合体的生长激素释放抑制因子类似物的特异性和选择性,如下所述。生长激素释放抑制因子类似物也在美国专利No.02210006790中有所公开。SSTR 1(如,Genbank登录号No.M81829),SSTR 2(如,Genbank登录号No.M81830),SSTR 3(如,Genbank登录号No.L07062)和SSTR 4(如,Genbank登录号No.AL049651)的基因片段完全编码序列和SSTR 5(如,Genbank登录号No.D16827)的cDNA克隆被亚克隆到哺乳动物表达载体pCMV上(Life Technologies,Lilano,Italy)。其它的SSTR序列是本领域技术人员公知的。稳定表达SSTR’s 1-5的克隆细胞系由使用磷酸钙共沉淀法(Davis L等人,1994,Basic methods inMolecular Biology,第二版,Appleton & Lange,Norwalk,CT,USA:611-646)转染至CHO-K1细胞中(ATCC,Manassas,Va,USA)而得到。pRSV-neo(ATCC)质粒作为可选择的标记被包含于其中。在含有0.5mg/ml G418(LifeTechnologies,Milano,Italy)的RPMI 1640介质中选择克隆细胞系,进行环克隆,并在培养物中扩增。
[0334]在冰冷的50mM Tris-HCl中将表达SSTR’s亚型的CHO-K1细胞匀化,在39000g(10分钟)离心分离两次,并立刻在新鲜的缓冲剂中进行再悬浮。最终的小颗粒在10mM Tris-HCl中进行再悬浮,以用于分析。
[0335]为了分析SSTR 1,3,4和5,使薄膜制剂的等分试样在25℃下与0.05nM[125I-Tyr11]SS-14在50mM HEPES(pH7.4)中温育90分钟,该HEPES含有10mg/ml牛血清白蛋白(BSA),5mM MgCl2,200KIU/ml抑肽酶(Trasylol),0.02mg/ml USP杆菌肽,和0.02mg/ml苯甲磺酰氟。最后的分析体积是0.3ml。
[0336]为分析SSTR 2,采用0.05nM[125I]MK-678为放射性配体,温育时间在25℃下为90分钟。使用Brandel过滤岐管通过GF/B玻璃微纤维过滤器(Whatman Co.)将其快速过滤,从而终止温育。然后用5ml冰冷缓冲剂的等分试样分别冲洗每个管和过滤器3次。特异性结合定义为放射性配体的结合总数减去出现在1000nM SS-14中的结合(对于SSTR 1,3,4和5)或1000nMMK-678中的结合(对于SSTR2)。
多巴胺受体特性和选择性分析
[0337]用于合成生长激素释放抑制因子-多巴胺嵌合体的多巴胺类似物的多巴胺-2受体的特性和选择性,取决于放射性配体结合试验,如下所述。
[0338]采用Brinkman Polytron细胞破碎仪(设定为6,15秒),在20ml冰冷的50mM Tris-HCl中匀化冷冻的鼠体纹状体(Zivic Laboratories,Pittsburgh,PA),得到粗膜。加入缓冲剂使终体积为40ml,在0-4℃下,匀浆在SorVal SS-34转子中以39000g离心分离10分钟。倒掉所得上层清液,再将小颗粒在冰冷的缓冲剂中匀化,在37℃下预先温育10分钟,如前述进行稀释和离心分离。在缓冲剂中再悬浮最终的小颗粒,并保存在冰上,用于受体结合分析试验。
[0339]为了进行分析,将洗涤过的薄膜制剂的等分试样和测试化合物与0.25nM[3HI]螺环哌啶酮(16.5Ci.mmol,New England Nuclear,Boston,MA)一起在50mM Tris HCl,120mM NaCl,5mM KCl,2mM CaCl2,1mM MgCl2中温育15分钟。最终的分析体积为1.0ml。使用Brandel过滤岐管通过GF/B玻璃纤维过滤器进行快速过滤,从而终止温育。然后用5ml冰冷缓冲剂的等分试样分别冲洗每个管和过滤器3次。特异性结合定义为放射性配体的结合总数减去出现在1000nM(+)丁克吗(butaclamol)中的结合。
对胞内产生cAMP的抑制
[0340]采用下列方法测定生长激素释放抑制因子测试化合物的激动活性。
[0341]将表达人类生长激素释放抑制因子(SRIF-14)亚型受体的CHO-K1细胞接种到24孔组织培养皿中,该培养皿处于含有10%胎牛血清(FCS)的RPMI 1640介质中。
[0342]用0.5ml RPMI 1640介质两次洗涤密度为105细胞/孔的细胞。向Hank’s平衡盐溶液中补充0.5mM 3-异丁基-1-甲基黄嘌呤(″IBMX″),然后在37℃下进行30分钟的细胞培养。在37℃下,于30分钟的时间内加入10μM佛司可林(forskolin,″FSK″)(Sigma Chemical Co.,St.Louis,MO),来激发环AMP的产生。
[0343]在加入FSK(10μM)前的5分钟,通过加入测试化合物(10-10M-10-6M)来测试化合物的激动剂作用。加入500μl冰冷的无水乙醇终止反应,然后将上清液转移到12×75mm的玻璃管中以测定cAMP。采用放射性免疫测定试剂盒(Perkin-Elmer,Boston,MA)测定cAMP。
其他实施方式
[0344]在不偏离本发明的范围和精神的条件下对本发明所述的方法和体系作出各种变更和变换,对本领域技术人员来说都是显而易见的。尽管已经与特定的实施例相联系而对本发明展开了描述,应该理解所要求保护的权利要求不应该被不适当地限制于这些特定的实施方式。事实上,对实施本发明的所述方式作出医药学、免疫学、药理学、内分泌学或相关领域的技术人员所显而易见的各种变化都应该属于本发明的范围。
[0345]将本说明书中提到的所有公开出版文献(包括PCT/US02/17859)并入本文作为参考,就像文中清楚地提供了每个独立公开出版的内容一样。
Claims (102)
1.一种嵌合类似物,其包括(1)与一种或多种生长激素释放抑制因子受体相结合的至少一个结构和(2)与一种或多种多巴胺受体相结合的至少一个结构,或其药学上可接受的盐。
2.根据权利要求1所述的嵌合类似物或其药学上可接受的盐,其中,所述的嵌合类似物包括式(I)结构,
其中,
X是H,Cl,Br,I,F,-CN,C1-10烷基,C1-10杂烷基,C2-10烯基,C2-10炔基,取代的C1-10烷基,取代的C1-10杂烷基,取代的C2-10烯基或取代的C2-10炔基;
R1是H,C1-10烷基,C1-10杂烷基,C2-10烯基,C2-10炔基,取代的C1-10烷基,取代的C1-10杂烷基,取代的C2-10烯基,取代的C2-10炔基或-CN;
R2和R3各自独立地为H或不存在,条件是当R2和R3不存在时,它们所连接的碳原子之间存在双键;
R4是H,C1-10烷基,C1-10杂烷基,C2-10烯基,C2-10炔基,取代的C1-10烷基,取代的C1-10杂烷基,取代的C2-10烯基或取代的C2-10炔基;
Y是-O-,-C(O)-,-S-,-S-(CH2)s-C(O)-,-S(O)-,-S(O)2-,-SC(O)-,-OC(O)-,-N(R5)-C(O)-或-N(R6)-;
当Y是-S-,-S(O)-,-S(O)2-,-O-或-N(R6)-时,L是-(CH2)p-C(O)-;或当Y是-N(R6)-,-O-或-S-时,L是-C(O)-(CR7R8)q-C(O)-;当Y是-C(O)-,SC(O)-,-OC(O)-,-S-(CH2)s-C(O)-或-N(R5)-C(O)-时,L是(氨基酸)t;
W是-CR9,R10-;
R5和R6各自独立地为H,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
R7,R8,R9和R10各自独立地为H,F,Cl,Br,I,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;或R7和R8可任选地连接在一起而形成环体系;或R9和R10可任选地连接在一起而形成环体系;
i是1-10,条件是当i为1时,则R1不为H,C1-4烷基,烯丙基,烯基或-CN,R4不为H或-CH3,R5,R6,R7和R8各自独立且不为H或C1-5烷基,L不为-(Doc)t-,X不为H,Cl,Br,I,F,-CN或C1-5烷基,或R9和R10各自独立且不为H;
m是0或1;
n是0-10;
p是1-10;
q是1-5;
s是1-10;
t是1-10;
Z是至少一种生长激素释放抑制因子受体的配体;以及
其中,括号之间的每一个结构在每次出现时均独立地连接到Z的N-末端或内部的氨基基团或羟基基团上。
3.根据权利要求1所述的嵌合类似物其药学上可接受的盐,其中,所述的嵌合类似物包括式(II)结构,
其中,
X是H,Cl,Br,I,F,-CN,C1-10烷基,C1-10杂烷基,C2-10烯基,C2-10炔基,取代的C1-10烷基,取代的C1-10杂烷基,取代的C2-10烯基,或取代的C2-10炔基;
R1是H,C1-10烷基,C1-10杂烷基,C2-10烯基,C2-10炔基,取代的C1-10烷基,取代的C1-10杂烷基,取代的C2-10烯基,取代的C2-10炔基,或-CN;
R2和R3各自独立地为H或不存在,条件是当R2和R3不存在时,它们所连接的碳原子之间存在双键;
R4是H,C1-10烷基,C1-10杂烷基,C2-10烯基,C2-10炔基,取代的C1-10烷基,取代的C1-10杂烷基,取代的C2-10烯基,或取代的C2-10炔基;
R5是H,C1-10烷基,C1-10杂烷基,C2-10烯基,C2-10炔基,取代的C1-10烷基,取代的C1-10杂烷基,取代的C2-10烯基,取代的C2-10炔基,或式-(CH2)rN(R11,R12)表示的基团;
Y是-O-,-C(O)-,-S-,-SC(O)-,-OC(O)-,-N(R6)-C(O)-,-N(R7)-,或-N(R8)-(CH2)s-C(O)-;
当Y是-S-,-O-或-N(R7)-时,L是-(CH2)p-C(O)-;或者,当Y是-N(R7)-,-O-,或-S-时,L是-C(O)-(CR9R10)q-C(O)-;或者,当Y是-C(O)-,SC(O)-,-OC(O)-,-N(R8)-(CH2)s-C(O)-,或-N(R6)-C(O)-时,L是(氨基酸)t;
W是-CR9,R10-;
R6,R7和R8各自独立地为H,C1-10烷基,取代的C1-10烷基,C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基,或取代的烷基芳基;
R9和R10各自独立地为H,Cl,Br,I,F,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基,或取代的烷基芳基;或者,R9和R10可任选地连接在一起形成环体系;
R11和R12各自独立地为H,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基,或取代的烷基芳基;
i是1-10,条件是当i为1时,R1不为H,C1-4烷基,烯丙基,烯基或-CN,R4不为H或-CH3,R5不为C1-5烷基基团或式-(CH2)rN(CH3)v的基团,R6,R7,R8,R9和R10各自独立且不为H或C1-5烷基,L不为-(Doc)t-,或者X不为H,Cl,Br,I,F,-CN,或C1-5烷基;
m是0或1;
n是2-10;
p是1-10;
q是1-5;
r是1-8;
s是1-10;
t是1-10;
v是2-4;
Z是至少一种生长激素释放抑制因子受体的配体;以及
其中,括号之间的每一个结构在每次出现时均独立地连接到Z的N-末端或内部的氨基基团或羟基基团上。
4.根据权利要求1所述的嵌合类似物或其药学上可接受的盐,其中,所述的嵌合类似物包括式(III)结构,
其中,
R2是H,-N(R11)N(R12,R13),-N(R6R7)或-COOH;
R4和R5各自独立地为H,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基,取代的烷基芳基或R8-C(O)-;
W是-CR9R10-或-(CH2)q-NH-(CH2)r-;
R1,R6,R7,R8,R11,R12和R13各自独立地为H,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
R9和R10各自独立地为H,-OH,-CN,-NO2,F,Cl,Br,I,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,烷基芳基,取代的烷基芳基或芳基;
X是C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,烷基芳基,取代的烷基芳基,芳基或酰基;
Q是C或N;条件是当Q是N时,R2不存在;
i是1-10;
n是1-6;
q是1-6;
r是1-8;
Z是至少一种生长激素释放抑制因子受体的配体;以及
其中,括号之间的每一个结构在每次出现时均独立地连接到Z的N-末端或内部的氨基基团或羟基基团上。
5.根据权利要求1所述的嵌合类似物或其药学上可接受的盐,其中,所述的嵌合类似物包括式(IV)结构,
其中,
R1和R2各自独立地为H,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
R3,R4,R5,R6和R7各自独立地为H,-OH,-CN,-NO2,F,Cl,Br,I,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
W是-CR4R5-;
Y是-(CR6R7)m-C(O)-或酰基;
m是0-10;
n是1-6;
Z是至少一种生长激素释放抑制因子受体的配体;以及
其中,括号之间的每一个结构在每次出现时均独立地连接到Z的N-末端或内部的氨基基团或羟基基团上。
6.根据权利要求1所述的嵌合类似物或其药学上可接受的盐,其中,所述的嵌合类似物包括式(V)结构,
其中,
P是-N(R3R4)或H;
X是N或S;
W是-CR5R6-;
Y是-(CR7R8)m-C(O)-;
R1,R3和R4各自独立地为H,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
R2,R5,R6,R7和R8各自独立地为H,-OH,-CN,-NO2,F,Cl,Br,I,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
i是1-10;
m是0-10;
n是0-6;
Z是至少一种生长激素释放抑制因子受体的配体;以及
其中,括号之间的每一个结构在每次出现时均独立地连接到Z的N-末端或内部的氨基基团或羟基基团上。
7.根据权利要求1所述的嵌合类似物或其药学上可接受的盐,其中,所述的嵌合类似物包括式(VI)结构,
其中,
Y是-(CR2R3)m-C(O)-或酰基;
R1是H,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
R2和R3各自独立地为H,-OH,-CN,-NO2,F,Cl,Br,I,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
i是1-10;
m是0-10;
Z是至少一种生长激素释放抑制因子受体的配体;以及
其中,括号之间的每一个结构在每次出现时均独立地连接到Z的N-末端或内部的氨基基团或羟基基团上。
8.根据权利要求1所述的嵌合类似物或其药学上可接受的盐,其中,所述的嵌合类似物包括式(VII)结构,
其中,
P是-N(R3R4)或H;
L是-(CR5R6)m-C(O)-或酰基;
Y是C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基,取代的烷基芳基或不存在;
R1,R2,R5和R6各自独立地为H,-OH,-CN,-NO2,F,Cl,Br,I,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
R3和R4各自独立地为H,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
i是1-10;
m是0-10;
Z是至少一种生长激素释放抑制因子受体的配体;以及
其中,括号之间的每一个结构在每次出现时均独立地连接到Z的N-末端或内部的氨基基团或羟基基团上。
9.根据权利要求1所述的嵌合类似物或其药学上可接受的盐,其中,所述的嵌合类似物包括式(VIII)结构,
其中,
X和Y各自独立地为-OH,-OR4或R5-C(O)-O-;
L是-(CR3R4)m-C(O)-或酰基;
R1,R2,R3和R4各自独立地为H,-OH,F,Cl,Br,I,-CN,NO2,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;或R2和R3可任选连接在一起而形成环体系;
R5是H,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
i是1-10;
m是0-10;
Z是至少一种生长激素释放抑制因子受体的配体;以及
其中,括号之间的每一个结构在每次出现时均独立地连接到Z的N-末端或内部的氨基基团或羟基基团上。
10.根据权利要求1所述的嵌合类似物或其药学上可接受的盐,其中,所述的嵌合类似物包括式(IX)结构,
(IX)
其中,
X和Y各自独立地为-OH,-OR4或R7-C(O)-;
Q是-(CR5R6)m-C(O)-或酰基;
R1,R2,R3,R4,R5和R6各自独立地为H,-OH,F,Cl,Br,I,-CN,NO2,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;或R1和R2可任选地连接在一起而形成环体系;或R3和R4可任选地连接在一起而形成环体系;
R7是H,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
i是1-10;
m是0-10;
Z是至少一种生长激素释放抑制因子受体的配体;以及
其中,括号之间的每一个结构在每次出现时均独立地连接到Z的N-末端或内部的氨基基团或羟基基团上。
11.根据权利要求1所述的嵌合类似物或其药学上可接受的盐,其中,所述的嵌合类似物包括式(X)结构,
其中,
Y是-(CR8R9)m-C(O)-或酰基;
R1,R2,R3,R4,R5,R6,R7,R8和R9各自独立地为H,-OH,F,Cl,Br,I,-CN,NO2,C1-10烷基,取代的C1-10烷基;C1-10杂烷基,取代的C1-10杂烷基,C2-10烯基,取代的C2-10烯基,C2-10炔基,取代的C2-10炔基,芳基,烷基芳基或取代的烷基芳基;
i是1-10;
m是0-10;
Z是至少一种生长激素释放抑制因子受体的配体;以及
其中,括号之间的每一个结构在每次出现时均独立地连接到Z的N-末端或内部的氨基基团或羟基基团上。
12.根据权利要求1所述的嵌合类似物或其药学上可接受的盐,其中,所述的嵌合类似物包括下式的化合物:
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Ac-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Ac-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop2-Lys(Ac)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Ac)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop3-Aepa-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-Aepa-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop6-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop7-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop8-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop9-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop10-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop11-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop12-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop13-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop6-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop7-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop8-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop9-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop10-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop11-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop12-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop13-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop6-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2
Dop7-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop8-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop9-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop10-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop11-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop12-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop13-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop5-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop6-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop7-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop8-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop9-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop10-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop11-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop12-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop13-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop5-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop6-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop7-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop8-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop9-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop10-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop11-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop12-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop13-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop5-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop6-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop7-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop8-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop9-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop10-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop11-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop12-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop13-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop5-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop6-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop7-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop8-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop9-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop10-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop11-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop12-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop13-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop5-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop6-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop7-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop8-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop9-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop10-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop11-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop12-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop13-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop1-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop1-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop4-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop4-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop5-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop6-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop7-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop8-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop9-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop10-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop11-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop12-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop13-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2
Dop3-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop4-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop5-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop6-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop7-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop8-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop9-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop10-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop11-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop12-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop13-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop1-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop2-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop3-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop4-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop1-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop2-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop3-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop4-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop5-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop6-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop7-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop8-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop9-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop10-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop11-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop12-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop13-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop1-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop2-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop3-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop4-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop1-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop2-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop3-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop4-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop5-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop6-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop7-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop8-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop9-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop10-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop11-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop12-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop13-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-SerBzl)-Tyr-NH2,
Dop5-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop6-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop7-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop8-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop9-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop10-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop11-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop12-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop13-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop5-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop6-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop7-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop8-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop9-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop10-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop11-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop12-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop13-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop5-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop6-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop7-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop8-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop9-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop10-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop11-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop12-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop13-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-Aepa-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-Aepa-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop1-Lys(Dop1)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop1-Lys(Dop1)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop1-Lys(Dop1)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop1-Lys(Dop1)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop1-Lys(Dop1)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop1-Lys(Dop1)-Lys-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop1-Lys(Dop1)-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop1-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop1-Lys(Dop2)-cyclo[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop1-Lys(Dop2)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop1-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-Aepa-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-Aepa-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-Aepa-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-Aepa-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop2-Lys(Dop2)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop2-Lys(Dop2)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop2-Lys(Dop2)-Lys-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop2-Lys(Dop2)-cyclo[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop2-Lys(Dop2)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop3-Lys(Dop3)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop3-Lys(Dop3)-Aepa-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop3-Lys(Dop3)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop3-Lys(Dop3)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop3-Lys(Dop3)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop3-DLys(Dop3)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop3-DLys(Dop3)-Aepa-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop3-DLys(Dop3)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop3-DLys(Dop3)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop3-DLys(Dop3)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop3-Lys(Dop3)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop3-Lys(Dop3)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop3-Lys(Dop3)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop3-Lys(Dop3)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop3-Lys(Dop3)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop3-Lys(Dop3)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop3-Lys(Dop3)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop3-Lys(Dop3)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop3-Lys(Dop3)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop3-Lys(Dop3)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop3-Lys(Dop3)-Lys-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop3-Lys(Dop3)-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop3-Lys(Dop3)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop3-Lys(Dop3)-cyclo[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop3-Lys(Dop3)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop3-Lys(Dop3)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop4-Lys(Dop4)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-Lys(Dop4)-Aepa-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-Lys(Dop4)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-Lys(Dop4)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-Lys(Dop4)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DLys(Dop4)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DLys(Dop4)-Aepa-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DLys(Dop4)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DLys(Dop4)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DLys(Dop4)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-Lys(Dop4)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop4-Lys(Dop4)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop4-Lys(Dop4)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop4-Lys(Dop4)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop4-Lys(Dop4)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop4-Lys(Dop4)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop4-Lys(Dop4)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop4-Lys(Dop4)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop4-Lys(Dop4)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop4-Lys(Dop4)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop4-Lys(Dop4)-Lys-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop4-Lys(Dop4)-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop4-Lys(Dop4)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop4-Lys(Dop4)-cyclo[Cys-Tyr-DTrp-Lys-Va]-Cys]-Trp-NH2,
Dop4-Lys(Dop4)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop4-Lys(Dop4)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DLys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DLys(Dop5)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DLys(Dop5)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DLys(Dop5)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop5-Lys(Dop5)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop5-Lys(Dop5)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop5-Lys(Dop5)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop5-Lys(Dop5)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop5-Lys(Dop5)-Lys-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop5-Lys(Dop5)-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop5-Lys(Dop5)-cyclo[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop5-Lys(Dop5)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop5-Lys(Dop5)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop6-Lys(Dop6)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop6-Lys(Dop6)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop6-Lys(Dop6)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop6-Lys(Dop6)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop6-DLys(Dop6)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop6-DLys(Dop6)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop6-DLys(Dop6)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop6-DLys(Dop6)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop6-Lys(Dop6)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop6-Lys(Dop6)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop6-Lys(Dop6)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop6-Lys(Dop6)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop6-Lys(Dop6)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop6-Lys(Dop6)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop6-Lys(Dop6)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop6-Lys(Dop6)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop6-Lys(Dop6)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop6-Lys(Dop6)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop6-Lys(Dop6)-Lys-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop6-Lys(Dop6)-DTyr-DTyr-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop6-Lys(Dop6)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop6-Lys(Dop6)-cyclo[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop6-Lys(Dop6)-Lys-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop6-Lys(Dop6)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop7-Lys(Dop7)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop7-Lys(Dop7)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop7-DLys(Dop7)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop7-DLys(Dop7)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop7-Lys(Dop7)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop7-Lys(Dop7)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop7-Lys(Dop7)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop7-Lys(Dop7)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop7-Lys(Dop7)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop7-Lys(Dop7)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop7-Lys(Dop7)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop7-Lys(Dop7)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop8-Lys(Dop8)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop8-Lys(Dop8)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop8-DLys(Dop8)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop8-DLys(Dop8)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop8-Lys(Dop8)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop8-Lys(Dop8)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop8-Lys(Dop8)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop8-Lys(Dop8)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop8-Lys(Dop8)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop8-Lys(Dop8)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop8-Lys(Dop8)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop8-Lys(Dop8)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop9-Lys(Dop9)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop9-Lys(Dop9)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop9-DLys(Dop9)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop9-DLys(Dop9)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop9-Lys(Dop9)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop9-Lys(Dop9)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop9-Lys(Dop9)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop9-Lys(Dop9)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop9-Lys(Dop9)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop9-Lys(Dop9)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop9-Lys(Dop9)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop9-Lys(Dop9)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop10-Lys(Dop10)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop10-Lys(Dop10)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop10-DLys(Dop10)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop10-DLys(Dop10)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop10-Lys(Dop10)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop10-Lys(Dop10)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop10-Lys(Dop10)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop10-Lys(Dop10)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop10-Lys(Dop10)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop10-Lys(Dop10)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop10-Lys(Dop10)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop10-Lys(Dop10)-cyclo[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop11-Lys(Dop11)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop11-Lys(Dop11)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop11-DLys(Dop11)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop11-DLys(Dop11)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop11-Lys(Dop11)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop11-Lys(Dop11)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop11-Lys(Dop11)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop11-Lys(Dop11)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop11-Lys(Dop11)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop11-Lys(Dop11)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop11-Lys(Dop11)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop11-Lys(Dop11)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop12-Lys(Dop12)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop12-Lys(Dop12)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop12-DLys(Dop12)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop12-DLys(Dop12)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop12-Lys(Dop12)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop12-Lys(Dop12)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop12-Lys(Dop12)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop12-Lys(Dop12)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop12-Lys(Dop12)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop12-Lys(Dop12)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop12-Lys(Dop12)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop12-Lys(Dop12)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop13-Lys(Dop13)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop13-Lys(Dop13)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop13-DLys(Dop10)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop13-DLys(Dop13)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop13-Lys(Dop13)-D2Nal-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop13-Lys(Dop13)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop13-Lys(Dop13)-DPhe-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop13-Lys(Dop13)-环[Cys-Tyr-DTrp-Lys-Thr-Cys]-2Nal-NH2,
Dop13-Lys(Dop13)-DPhe-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop13-Lys(Dop13)-环[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-ol,
Dop13-Lys(Dop13)-DPhe-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop13-Lys(Dop13)-环[Cys-Tyr-DTrp-Lys-Val-Cys]-Trp-NH2,
Dop1-Lys(Dop1)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop1-Lys(Dop1)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop1-DLys(Dop1)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop1-DLys(Dop1)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop1-Lys(Dop1)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop1-Lys(Dop1)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop1-DLys(Dop1)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop1-DLys(Dop1)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop1-Lys(Dop1)-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop1-Lys(Dop1)-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop1-DLys(Dop1)-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop1-DLys(Dop1)-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop1-Lys(Dop1)-Lys-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop1-Lys(Dop1)-Lys-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop1-DLys(Dop1)-Lys-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop1-DLys(Dop1)-Lys-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop2-Lys(Dop2)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop2-Lys(Dop2)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop2-DLys(Dop2)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop2-DLys(Dop2)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop2-Lys(Dop2)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop2-Lys(Dop2)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop2-DLys(Dop2)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop2-DLys(Dop2)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop2-Lys(Dop2)-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop2-Lys(Dop2)-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop2-DLys(Dop2)-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop2-DLys(Dop2)-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop2-Lys(Dop2)-Lys-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop2-Lys(Dop2)-Lys-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop2-DLys(Dop2)-Lys-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop2-DLys(Dop2)-Lys-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop3-Lys(Dop3)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop3-Lys(Dop3)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop3-Lys(Dop3)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop3-Lys(Dop3)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop3-Lys(Dop3)-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop3-Lys(Dop3)-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop3-DLys(Dop3)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop3-DLys(Dop3)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop3-DLys(Dop3)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop3-DLys(Dop3)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop3-DLys(Dop3)-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop3-DLys(Dop3)-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop4-Lys(Dop4)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop4-Lys(Dop4)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop4-Lys(Dop4)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop4-Lys(Dop4)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop4-Lys(Dop4)-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2
Dop4-Lys(Dop4)-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2
Dop4-Lys(Dop4)-Lys-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop4-Lys(Dop4)-Lys-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop4-DLys(Dop4)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop4-DLys(Dop4)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop4-DLys(Dop4)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop4-DLys(Dop4)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop4-DLys(Dop4)-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop4-DLys(Dop4)-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop4-DLys(Dop4)-Lys-Aepa-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop4-DLys(Dop4)-Lys-Aepa-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop5-Lys(Dop5)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop5-Lys(Dop5)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop5-DLys(Dop5)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop5-DLys(Dop5)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop5-Lys(Dop5)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop5-Lys(Dop5)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop5-DLys(Dop5)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop5-DLys(Dop5)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop6-Lys(Dop6)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop6-Lys(Dop6)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop6-DLys(Dop6)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop6-DLys(Dop6)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop6-Lys(Dop6)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop6-Lys(Dop6)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop6-DLys(Dop6)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop6-DLys(Dop6)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop7-Lys(Dop7)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop7-Lys(Dop7)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop7-Lys(Dop7)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop7-Lys(Dop7)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop8-Lys(Dop8)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop8-Lys(Dop8)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop8-Lys(Dop8)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop8-Lys(Dop8)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop9-Lys(Dop9)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop9-Lys(Dop9)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop9-Lys(Dop9)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop9-Lys(Dop9)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop10-Lys(Dop10)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop10-Lys(Dop10)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop10-Lys(Dop10)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop10-Lys(Dop10)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop11-Lys(Dop11)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop11-Lys(Dop11)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop11-Lys(Dop11)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop11-Lys(Dop11)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop12-Lys(Dop12)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop12-Lys(Dop12)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop12-Lys(Dop12)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop12-Lys(Dop12)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop13-Lys(Dop13)-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop13-Lys(Dop13)-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop13-Lys(Dopl3)-Lys-Caeg-环[DCys-3Pal-DTrp-Lys-DCys]-Thr(Bzl)-Tyr-NH2,
Dop13-Lys(Dop13)-Lys-Caeg-环[DCys-Phe-DTrp-Lys-DCys]-Ser(Bzl)-Tyr-NH2,
Dop1-Lys(Dop1)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop1-Lys(Dop1)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop1-DLys(Dop1)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop2-DLys(Dop2)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-Lys(Dop3)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop3-Lys(Dop3)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-Lys(Dop3)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop4-Lys(Dop4)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop4-Lys(Dop4)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop4-Lys(Dop4)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop5-DLys(Dop5)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop5-DLys(Dop5)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop5-DLys(Dop5)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop6-Lys(Dop6)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop6-Lys(Dop6)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop6-DLys(Dop6)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop6-DLys(Dop6)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop6-Lys(Dop6)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop6-DLys(Dop6)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop7-Lys(Dop7)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop7-Lys(Dop7)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop7-Lys(Dop7)-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop8-Lys(Dop8)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop8-Lys(Dop8)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop9-Lys(Dop9)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop9-Lys(Dop9)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop10-Lys(Dop10)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop10-Lys(Dop10)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop11-Lys(Dop11)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop11-Lys(Dop11)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop12-Lys(Dop12)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop12-Lys(Dop12)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop13-Lys(Dop13)-环[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-NH2,
Dop13-Lys(Dop13)-DPhe-环[Cys-Phe-(N-Me)DTrp-Lys-Thr-Cys]-Thr-、NH2,
Dop1-DPhe-环[Cys-3ITyr(Dop1)-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop1-DPhe-Doc-DPhe-环[Cys-3ITyr(Dop1)-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-DPhe-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-
NH2,Dop1-Lys(Dop1)-DPhe-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop1-Lys(Dop1)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop1-DLys(Dop1)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-Aepa-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-3ITyr-DTr-Lys-Thr-Cys]-Thr-NH2
Dop2-Lys(Dop2)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-Aepa-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop3-Lys(Dop3)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop4-Lys(Dop4)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-Lys(Dop3)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop4-Lys(Dop4)-Aepa-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop5-DLys(Dop5)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop5-DLys(Dop5)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop5-DLys(Dop5)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop5-DLys(Dop5)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop5-DLys(Dop5)-DPhe-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DLys(Dop5)-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DLys(Dop5)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DLys(Dop5)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DLys(Dop5)-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop5-DLys(Dop5)-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop5-DLys(Dop5)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop5-DLys(Dop5)-Lys-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop6-Lys(Dop6)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop7-Lys(Dop7)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop8-Lys(Dop8)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop9-Lys(Dop9)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop10-Lys(Dop10)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop11-Lys(Dop11)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop12-Lys(Dop12)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop13-Lys(Dop13)-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop6-Lys(Dop6)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop7-Lys(Dop7)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop8-Lys(Dop8)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop9-Lys(Dop9)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop10-Lys(Dop10)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop11-Lys(Dop11)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop12-Lys(Dop12)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,或
Dop13-Lys(Dop13)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2。
13.根据权利要求1所述的嵌合类似物或其药学上可接受的盐,其中,所述的嵌合类似物包括下式的化合物:
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Ac-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Ac-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,或
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2。
14.根据权利要求1所述的嵌合类似物或其药学上可接受的盐,其中,所述的嵌合类似物包括下式的化合物:
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2或
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2。
15.根据权利要求14所述的嵌合类似物或其药学上可接受的盐,其中,所述的嵌合类似物包括下式的化合物:
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2。
16.根据权利要求14所述的嵌合类似物或其药学上可接受的盐,其中,所述的嵌合类似物包括下式化合物:
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2。
17.根据权利要求14所述的嵌合类似物或其药学上可接受的盐,其中,所述的嵌合类似物包括下式化合物:
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2。
18.根据权利要求1所述的嵌合类似物或其药学上可接受的盐,其中,所述的嵌合类似物包括下式的化合物:
Dop2-Lys(Dop2)-DTyr-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],
Dop2-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],或
Dop2-DTyr-DTyr-Caeg-环[DCys-3Pal-DTrp-Lys-Dcys]-Thr(Bzl)-Tyr-NH2。
20.一种在需要的患者体内引起多巴胺受体激动作用的方法,其中,所述的方法包括以有效量的本发明嵌合类似物向所述的患者给药,其中所述的嵌合类似物包括式(I),(II),(III),(IV),(V),(VI)(VII),(VIII),(IX)或(X)的化合物或其药学上可接受的盐,或中间体化合物(3),(6),(11),(14),(18),(21),(24)或(27)或其有机盐或无机盐;以及
其中所述的有效量是能在所述的患者体内有效地引起多巴胺受体激动作用的用量。
21.根据权利要求20所述的方法,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Ac-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Ac-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,或
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2。
22.根据权利要求21所述的方法,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,或
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2。
23.根据权利要求22所述的方法,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2。
24.根据权利要求22所述的方法,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2。
25.根据权利要求22所述的方法,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2。
26.根据权利要求20所述的方法,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-Lys(Dop2)-DTyr-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],
Dop2-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],或
Dop2-DTyr-DTyr-Caeg-环[DCys-3Pal-DTrp-Lys-Dcys]-Thr(Bzl)-Tyr-NH2。
27.一种在需要的患者体内引起生长激素释放抑制因子受体激动作用的方法,其中,所述的方法包括以有效量的本发明嵌合类似物向所述患者给药,其中所述的嵌合类似物包括式(I),(II),(III),(IV),(V),(VI)(VII),(VIII),(IX)或(X)的化合物或其药学上可接受的盐,或中间体化合物(3),(6),(11),(14),(18),(21),(24)或(27)或其有机盐或无机盐;以及
其中所述的有效量为能在所述患者体内有效地引起生长激素释放抑制因子受体激动作用的用量。
28.根据权利要求27所述的方法,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Ac-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Ac-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,或
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2。
29.根据权利要求28所述的方法,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2;或
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2。
30.根据权利要求29所述的方法,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2。
31.根据权利要求29所述的方法,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2。
32.根据权利要求29所述的方法,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2。
33.根据权利要求27所述的方法,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-Lys(Dop2)-DTyr-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],
Dop2-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],或
Dop2-DTyr-DTyr-Caeg-环[DCys-3Pal-DTrp-Lys-Dcys]-Thr(Bzl)-Tyr-NH2。
34.一种在需要的患者体内既引起多巴胺受体激动作用又引起生长激素释放抑制因子受体激动作用的方法,其中所述的方法包括以有效量的本发明嵌合类似物向所述的患者给药,其中所述的嵌合类似物包括式(I),(II),(III),(IV),(V),(VI),(VII),(VIII),(IX)或(X)的化合物或其药学上可接受的盐;权利要求12所述的化合物或其药学上可接受的盐;或中间体化合物(3),(6),(11),(14),(18),(21),(24)或(27)或其有机盐或无机盐;以及
其中所述的有效量是能在所述患者体内有效地引起多巴胺受体和生长激素释放抑制因子受体激动作用的用量。
35.根据权利要求34所述的方法,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Ac-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Ac-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,或
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2。
36.根据权利要求35所述的方法,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2;或
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2。
37.根据权利要求36所述的方法,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2。
38.根据权利要求36所述的方法,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2。
39.根据权利要求36所述的方法,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2。
40.根据权利要求34所述的方法,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-Lys(Dop2)-DTyr-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],
Dop2-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],或
Dop2-DTyr-DTyr-Caeg-环[DCys-3Pal-DTrp-Lys-Dcys]-Thr(Bzl)-Tyr-NH2。
41.一种药物组合物,其包括有效量的式(I),(II),(III),(IV),(V),(VI)(VII),(VIII),(IX)或(X)的化合物或其药学上可接受的盐,以及药学上可接受的载体;权利要求12所述的化合物或其药学上可接受的盐;或中间体化合物(3),(6),(11),(14),(18),(21),(24)或(27)或其有机盐或无机盐;其中所述的有效量是能在需要的患者体内有效地引起多巴胺受体激动作用或有效地引起生长激素释放抑制因子受体激动作用或有效地引起上述两种激动作用的用量。
42.根据权利要求41所述的药物组合物,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Ac-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Ac-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,或
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2。
43.根据权利要求42所述的药物组合物,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2;或
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2。
44.根据权利要求43所述的药物组合物,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2。
45.根据权利要求43所述的药物组合物,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2。
46.根据权利要求43所述的药物组合物,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2。
47.根据权利要求41所述的药物组合物,其中,所述的嵌合类似物包括下式的化合物或其药学上可接受的盐:
Dop2-Lys(Dop2)-DTyr-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],
Dop2-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],或
Dop2-DTyr-DTyr-Caeg-环[DCys-3Pal-DTrp-Lys-Dcys]-Thr(Bzl)-Tyr-NH2。
48.一种治疗患者所患有的疾病或病症的方法,所述方法包括以治疗有效量的嵌合类似物向所述患者给药,其中所述的嵌合类似物包括式(I),(II),(III),(IV),(V),(VI)(VII),(VIII),(IX)或(X)的化合物或其药学上可接受的盐;
权利要求12所述的化合物或其药学上可接受的盐;或
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Ac-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Ac-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],
Dop2-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],或
Dop2-DTyr-DTyr-Caeg-环[DCys-3Pal-DTrp-Lys-Dcys]-Thr(Bzl)-Tyr-NH2;或
其药学上可接受的盐;或
中间体化合物(3),(6),(11),(14),(18),(21),(24)或(27)或其有机盐或无机盐;以及
其中所述的疾病或病症选择下列:
神经内分泌肿瘤;
血管疾病;
结缔组织疾病;
免疫性疾病;
胃肠道,胰腺,肾脏或肝脏疾病;
代谢性疾病;
恶疾;
肺部、乳腺、前列腺、肝脏、甲状腺、血液的癌症或肿瘤;
肌与骨胳疾病;
恐慌症;和
鸦片用药过量;以及
其中所述的治疗有效量是指有效地治疗所述患者所患有的疾病或病症的用量。
49.根据权利要求48所述的方法,其中,所述的神经内分泌肿瘤是垂体的神经内分泌肿瘤。
50.根据权利要求49所述的方法,其中,所述的垂体的神经内分泌肿瘤是产生ACTH的肿瘤。
51.根据权利要求50所述的方法,其中,所述产生ACTH的肿瘤的病症是Cushing’s疾病。
52.根据权利要求49所述的方法,其中,所述的垂体的神经内分泌肿瘤是产生生长激素的肿瘤。
53.根据权利要求52所述的方法,其中,所述的产生生长激素的肿瘤的病症是肢端肥大症。
54.根据权利要求49所述的方法,其中,所述的垂体的神经内分泌肿瘤是产生催乳激素的肿瘤。
55.根据权利要求54所述的方法,其中,所述产生催乳激素的肿瘤这一病症是催乳素瘤。
56.根据权利要求49所述的方法,其中,所述的垂体的神经内分泌肿瘤是高催乳素血症。
57.根据权利要求49所述的方法,其中,所述的垂体的神经内分泌肿瘤是促甲状腺激素(TSH)分泌肿瘤。
58.根据权利要求49所述的方法,其中,所述的垂体的神经内分泌肿瘤是“无功能的”垂体腺瘤。
59.根据权利要求49所述的方法,其中,所述的垂体的神经内分泌肿瘤是促性腺素瘤。
60.根据权利要求48所述的方法,其中,所述的神经内分泌肿瘤是良性肿瘤。
61.根据权利要求60所述的方法,其中,所述的良性肿瘤导致类癌综合症。
62.根据权利要求48所述的方法,其中,所述的神经内分泌肿瘤是胰升糖素瘤。
63.根据权利要求48所述的方法,其中,所述的神经内分泌肿瘤是小细胞肺癌。
64.根据权利要求48所述的方法,其中,所述的神经内分泌肿瘤是甲状腺髓样癌。
65.根据权利要求48所述的方法,其中,所述的神经内分泌肿瘤是VIP肿瘤。
66.根据权利要求48所述的方法,其中,所述的神经内分泌肿瘤是胰岛素瘤。
67.根据权利要求48所述的方法,其中,所述的血管疾病是不适当的血管生成。
68.根据权利要求48所述的方法,其中,所述的血管疾病是再狭窄。
69.根据权利要求48所述的方法,其中,所述的血管疾病是视网膜病。
70.根据权利要求48所述的方法,其中,所述的视网膜病是糖尿病性视网膜病。
71.根据权利要求69所述的方法,其中,所述的视网膜病是增生性视网膜病。
72.根据权利要求69所述的方法,其中,其中所述的视网膜病是黄斑变性。
73.根据权利要求72所述的方法,其中,所述的黄斑变性是与年龄相关的黄斑变性。
74.根据权利要求48所述的方法,其中,所述的结缔组织疾病是硬皮病。
75.根据权利要求48所述的方法,其中,所述的免疫性疾病是风湿性关节炎。
76.根据权利要求48所述的方法,其中,所述的免疫性疾病是炎症。
77.根据权利要求48所述的方法,其中,所述的免疫性疾病是纤维化。
78.根据权利要求48所述的方法,其中,所述的免疫性疾病是Graves’眼病。
79.根据权利要求48所述的方法,其中,所述的免疫性疾病是同种异体移植物排斥。
80.根据权利要求48所述的方法,其中,所述的胃肠道疾病包括胃酸分泌,胃溃疡,炎症性肠病(IBD)或痢疾。
81.根据权利要求80所述的方法,其中,所述的IBD是肠易激综合症或Crohn’s疾病。
82.根据权利要求48所述的方法,其中,所述的代谢性疾病包括高脂血症,胰岛素抵抗性,X综合症,肥胖症,糖尿病或糖尿病相关性疾病。
83.根据权利要求82所述的方法,其中,所述的糖尿病相关性疾病包括糖尿病性肾病,糖尿病性神经病,糖尿病性视网膜病或胃轻瘫。
84.根据权利要求48所述的方法,其中,所述的恶疾是心脏恶疾,癌性恶疾或衰老性恶疾。
85.根据权利要求58-84任意一项所述的方法,其中,所述的嵌合类似物包括SSTR-1激动剂和多巴胺受体激动剂;或其药学上可接受的盐。
86.根据权利要求85所述的方法,其中,所述的嵌合类似物进一步包括SSTR-2激动剂。
87.根据权利要求85所述的方法,其中,所述的嵌合类似物进一步包括SSTR-3激动剂。
88.根据权利要求86所述的方法,其中,所述的嵌合类似物进一步包括SSTR-3激动剂。
89.根据权利要求85所述的方法,其中,所述的嵌合类似物进一步包括SSTR-5激动剂。
90.根据权利要求86所述的方法,其中,所述的嵌合类似物进一步包括SSTR-5激动剂。
91.根据权利要求87所述的方法,其中,所述的嵌合类似物进一步包括SSTR-5激动剂。
92.根据权利要求88所述的方法,其中,所述的嵌合类似物进一步包括SSTR-5激动剂。
93.根据权利要求48-84中任意一项所述的方法,其中,所述的嵌合类似物包括SSTR-2激动剂和多巴胺受体激动剂,或其药学上可接受的盐。
94.根据权利要求93所述的方法,其中,所述的嵌合类似物进一步包括SSTR-5激动剂。
95.根据权利要求48-84中任意一项所述的方法,其中,所述的嵌合类似物包括SSTR-3激动剂和多巴胺受体激动剂,或其药学上可接受的盐。
96.根据权利要求48-84中任意一项所述的方法,其中,所述的嵌合类似物包括SSTR-5激动剂和多巴胺受体激动剂,或其药学上可接受的盐。
97.一种对需要的患者所患有的肢端肥大症进行治疗的方法,其中,所述的方法包括以治疗有效量的嵌合类似物向所述的患者给药,其中所述的嵌合类似物包括式(I),(II),(III),(IV),(V),(VI)(VII),(VIII),(IX)或(X)的化合物或其药学上可接受的盐;
权利要求12所述的化合物或其药学上可接受的盐;或
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Ac-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Ac-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],
Dop2-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],或
Dop2-DTyr-DTyr-Caeg-环[DCys-3Pal-DTrp-Lys-Dcys]-Thr(Bzl)-Tyr-NH2;或
其药学上可接受的盐;或
中间体化合物(3),(6),(11),(14),(18),(21),(24)或(27)或其有机盐或无机盐;以及
其中所述的治疗有效量是指有效地治疗所述患者所患右的肢端肥大症的用量。
98.根据权利要求97所述的方法,其中,所述的嵌合类似物包括SSTR-5激动剂和多巴胺受体激动剂。
99.根据权利要求98所述的方法,其中,所述的嵌合类似物进一步包括SSTR-2激动剂。
100.一种对需要的患者所患的催乳素血症进行治疗的方法,其中,所述的方法包括以治疗有效量的嵌合类似物向所述患者给药,其中所述的嵌合类似物包括式(I),(II),(III),(IV),(V),(VI)(VII),(VIII),(IX)或(X)的化合物或其药学上可接受的盐;或
权利要求12所述的化合物或其药学上可接受的盐;或
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-DPhe-Doc-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Ac-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Ac-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop3-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop4-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop5-Lys(Dop5)-DPhe-环[Cys-Tyr-DTrp-Lys-Abu-Cys]-Thr-NH2,
Dop2-DPhe-环[Cys-3ITyr(Dop2)-DTrp-Lys-Val-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-DTyr-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-DLys(Dop2)-DPhe-环[Cys-3ITyr-DTrp-Lys-Thr-Cys]-Thr-NH2,
Dop2-Lys(Dop2)-DTyr-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],
Dop2-Tyr-环[DDab-Arg-Phe-Phe-DTrp-Lys-Thr-Phe],或
Dop2-DTyr-DTyr-Caeg-环[DCys-3Pal-DTrp-Lys-Dcys]-Thr(Bzl)-Tyr-
NH2;或
其药学上可接受的盐;或
中间体化合物(3),(6),(11),(14),(18),(21),(24)或(27)或其有机盐或无机盐;以及
其中所述的治疗有效量是有效地治疗所述患者所患有的催乳素血症的用量。
101.根据权利要求100所述的方法,其中,所述的嵌合类似物包括SSTR-5激动剂和多巴胺受体激动剂。
102.根据权利要求101所述的方法,其中,所述的嵌合类似物进一步包括SSTR-2激动剂。
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CN110105232A (zh) * | 2019-05-10 | 2019-08-09 | 中国农业大学 | 一种金刚烷胺半抗原及其制备方法和应用 |
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US7517853B2 (en) * | 2003-04-11 | 2009-04-14 | Ipsen Pharma S.A.S. | Somatostatin-dopamine chimeric analogs |
EP2084178B1 (en) * | 2006-10-20 | 2011-12-07 | Ipsen Pharma S.A.S. | Peptide-cytotoxic conjugates |
GB0721333D0 (en) * | 2007-10-31 | 2007-12-12 | Motac Neuroscience Ltd | Medicaments |
AU2009246894A1 (en) * | 2008-05-14 | 2009-11-19 | Ipsen Pharma S.A.S. | Pharmaceutical compositions of somatostatin-dopamine conjugates |
WO2011104627A1 (en) | 2010-02-24 | 2011-09-01 | Ipsen Pharma S.A.S. | Metabolites of dop2-d-lys(dop2)-cyclo[cys-tyr-d-trp-lys-abu-cys]-thr-nh2 |
RU2457215C1 (ru) * | 2011-04-07 | 2012-07-27 | Закрытое Акционерное Общество "Фарм-Синтез" | Октапептид для получения радиофармацевтических средств, радиофармацевтическое средство на его основе и способ диагностики опухолей, экспрессирующих соматостатиновые рецепторы |
AU2012356321B2 (en) | 2011-12-23 | 2015-09-17 | Ipsen Manufacturing Ireland Limited | Process for the synthesis of therapeutic peptides |
CN102898397B (zh) * | 2012-09-26 | 2014-12-10 | 江苏华益科技有限公司 | (4aR,10bR)-3,4,4a,5,6,10b-六氢-2H-萘并[1,2-b][1,4]噁嗪-9-醇类物质及其盐酸盐合成方法 |
WO2014070965A2 (en) | 2012-11-01 | 2014-05-08 | Ipsen Pharma S.A.S | Somatostatin analogs and dimers thereof |
TWI523863B (zh) | 2012-11-01 | 2016-03-01 | 艾普森藥品公司 | 體抑素-多巴胺嵌合體類似物 |
RU2528414C1 (ru) * | 2013-01-25 | 2014-09-20 | Закрытое Акционерное Общество "Фарм-Синтез" | Циклический октапептид, радиофармацевтическое средство на его основе и способ применения радиофармацевтического средства для получения лекарственных (фармацевтических) средств для лечения новообразований, экспрессирующих соматостатиновые рецепторы |
BR112017015487A2 (pt) | 2015-01-20 | 2018-01-30 | Xoc Pharmaceuticals Inc | Composto; composição; método de tratamento e/ou prevenção de enxaqueca, als, doença de alzheimer, doença de parkinson, distúrbios extrapirimidais, depressão, náusea, êmese, síndrome das pernas inquietas, insônia, agressão, doença de huntington, doença cardiopulmonar, fibrogênese, hipertensão arterial pulmonar, ansiedade, dependências a drogas, distonia, parassonia ou hiperlactinemia em um indivíduo; métodos de agonização dos receptores d2, 5-ht1d, 5-ht1a e 5-ht2c, em um indivíduo; método de antagonização do receptor d3 em um indivíduo; métodos de agonização seletiva dos receptores 5 -ht1d, e 5-ht2c, método de fornecimento de atividade de antagonista funcional no receptor 5 -ht2b ou no receptor 5-ht7, ou em ambos, em um indivíduo; método de fornecimento de atividade de antagonista funcional nos receptores adrenérgicos em um indivíduo |
CA2974113A1 (en) | 2015-01-20 | 2016-07-28 | Xoc Pharmaceuticals, Inc. | Isoergoline compounds and uses thereof |
EP3495363B1 (en) * | 2016-07-28 | 2023-08-23 | Shionogi & Co., Ltd | Nitrogen-containing condensed ring compounds having dopamine d3 receptor antagonistic effect |
CA3064274A1 (en) | 2017-06-01 | 2018-12-06 | Xoc Pharmaceuticals, Inc. | Ergoline derivatives for use in medicine |
WO2019146740A1 (ja) | 2018-01-26 | 2019-08-01 | 塩野義製薬株式会社 | ドーパミンd3受容体拮抗作用を有する環式化合物 |
CN111801330B (zh) | 2018-01-26 | 2024-04-05 | 盐野义制药株式会社 | 具有多巴胺d3受体拮抗作用的稠环化合物 |
GB2590341A (en) * | 2019-10-04 | 2021-06-23 | Tiburio Therapeutics Inc | Storage stable somatostatin-dopamine chimeric compounds and salt forms thereof |
WO2023235232A2 (en) * | 2022-05-31 | 2023-12-07 | The Administrators Of The Tulane Educational Fund | Glycosylated cyclic endomorphin analogs |
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DE652720C (de) | 1932-12-03 | 1937-11-09 | Pirelli | Elektrische OElkabelanlage mit Druckausgleichsbehaelter und zusaetzlichem hydrostatischem Speisebehaelter |
CH652720A5 (en) * | 1983-02-16 | 1985-11-29 | Sandoz Ag | Ergoline derivatives, their preparation and use |
WO2000004916A1 (en) | 1998-07-23 | 2000-02-03 | Societe De Conseils De Recherches Et D'applications Scientifiques Sas | Encapsulation of water soluble peptides |
EP1379526A1 (en) * | 2001-04-16 | 2004-01-14 | Finetech Laboratories Ltd. | Process and intermediates for production of cabergoline and related compounds |
EP2062914B1 (en) * | 2001-06-08 | 2014-05-07 | Ipsen Pharma | Somatostatin-dopamine chimeric analogs |
US7517853B2 (en) * | 2003-04-11 | 2009-04-14 | Ipsen Pharma S.A.S. | Somatostatin-dopamine chimeric analogs |
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CN110105232A (zh) * | 2019-05-10 | 2019-08-09 | 中国农业大学 | 一种金刚烷胺半抗原及其制备方法和应用 |
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