CN111533702A - 上调神经肽pacap及其受体pac1-r的小分子化合物spam1及制备方法和用途 - Google Patents
上调神经肽pacap及其受体pac1-r的小分子化合物spam1及制备方法和用途 Download PDFInfo
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Abstract
本发明公开了上调神经肽PACAP及其受体PAC1‑R的小分子化合物SPAM1及制备方法和用途，其结构如式（Ⅰ）所示，其中R=无或H20或HCl；本发明的SPAM1分子量小，能高效穿越生物学屏障，包括血脑屏障、血睾屏障等；本发明的SPAM1正反馈上调下丘脑‑垂体分泌的神经递质/调质PACAP及其特异受体PAC1‑R的表达，作用于性腺轴和肾上腺轴的下游腺体，因此其调控作用是全面的；本发明的SPAM1特异靶向PAC1‑R1，仅作用于天然表达PAC1‑R神经系统与内分泌系统的细胞和组织，副作用较小。因此，SPAM1将成为有效治疗与预防与神经肽PACAP密切相关的，神经系统、内分泌系统及免疫系统功能衰老与紊乱的新型小分子化合药物。
Description
技术领域
本发明涉及化学与生物化学领域，具体地说，涉及有效上调神经肽垂体腺苷酸环化酶激活多肽(pituitary adenylate cyclase activating polypeptide，PACAP)及其特异受体PAC1-R表达的小分子化合物SPAM1：4-((4-(4-氧-3,4-二氢喹唑啉-2-基)丁酰)甲基苯甲酸及其衍生物，SPAM1的高效制备方法及其在预防与治疗与PACAP及其特异受体PAC1-R相关的神经系统、内分泌系统、与免疫系统的生理病理疾病和功能衰退的的应用。
背景技术
最初从牛的下丘脑-垂体中分离得到的神经肽PACAP属于血管活性肠肽/分泌素/生长激素释放激素/胰高血糖素超家族；PACAP在进化过程中极其其保守的活性肽，青蛙和人的PACAP只有一个氨基酸的差异【1】。PACAP通过三个B类G蛋白偶联受体介导了发挥重要的调控神经系统、内分泌系统和免疫系统的功能：一个PACAP特异受体PAC1-R和两个和血管活性肠肽共享受体VPAC1-R和VPAC2-R。作为重要的神经递质和神经调质，PACAP的随龄下调被认为是衰老的原因之一。
PACAP及其受体，尤其其特异PAC1-R不仅在下丘脑-垂体高密度分布，而且在垂体-肾上腺轴、垂体-性腺轴、松果体和胸腺等神经内分泌组织和腺体，包括肾上腺、睾丸和卵巢上高密度分布，介导了相关应激激素、性激素和免疫因子的分泌和调节；包括上调促肾上腺皮质激素释放激素(corticotropin releasing hormone，CRH)和肾上腺皮质酮(corticosterone，COR)，参与调节褪黑素和促性腺激素释放激素(gonadotrophinreleasing hormone，GnRH)释放，上调睾酮(testosterone，TE)和雌二醇(estradiol,E2)；而PACAP缺失的动物胸腺衰退，免疫功能下调。总而言之，现有细胞和动物研究均表明：PACAP及PAC1-R介导机体的应激调控、增强雄性和雌性的性功能和生殖能力、促进免疫功能、有效降低脓毒症死亡率。
虽然PACAP具有潜在的抗衰老的药用开发价值，但鉴于PACAP的体内稳定性极差，例如PACAP38的体内半衰期少于2min，而且其穿越生物屏障的功能有限，因此直接把PACAP开发成药被极大的限制。
小分子SPAM1(4-((4-(4-氧-3,4-二氢喹唑啉-2-基)丁酰)甲基苯甲酸)是我们通过靶向位于PAC1-R的N端胞外域的别构调节位点，通过计算机虚拟筛选、并经过细胞水平和动物水平验证获得的PAC1-R小分子别构调节剂。
我们最新的细胞学和动物学研究首次发现SPAM1可以正反馈地、浓度依赖地上调体内PACAP及其靶器官中PACAP特异受体PAC1-R的表达，后续利用D-半乳糖诱导的小鼠衰老模型的动物实验首次确证SPAM1可以通过上调PACAP/PAC1-R信号通路发挥调控垂体-肾上腺轴、垂体-性腺轴和胸腺的功能，抵抗因PACAP下调导致的机体衰退，具体作用包括：1)上调机体应激能力，2)增强性功能和繁殖能力，及3)抵抗免疫功能低下。
发明内容
本发明的目的是在于提供一个能够有效上调体内PACAP及其特异受体PAC1-R表达的小分子SPAM1。
为了实现上述目的，本发明采用如下技术方案：
上调神经肽PACAP及其受体PAC1-R的小分子化合物SPAM1，其结构如式(Ⅰ)所示，其中R＝无或H20或HCl(无修饰或水合化修饰或盐酸化修饰)；
具有下述结构的化合物SPAM1-3(式(Ⅱ)，A-C)；
上述小分子化合物SPAM1的制备方法，是分两步合成(式(Ⅲ)I,II)，包括如下步骤：
(1)2-氨基苯甲酰胺(A)和戊二酸酐(B)聚合反应获得基础化合物4-(4-氧-3,4-二氢喹唑啉-2-基)丁酸(C)；
(2)4-(4-氧-3,4-二氢喹唑啉-2-基)丁酸(C)再和苯并[d][1,2,3]三唑-1-醇(D)、4-(氨甲基)苯甲酸(E)和三乙胺(F)缩合而成；
上述小分子化合物SPAM1在制备预防或治疗与神经肽PACAP密切相关的，神经系统、内分泌系统或免疫系统功能衰老与紊乱的药物中的应用。
上述小分子化合物SPAM1在制备预防或治疗下丘脑-垂体-肾上腺轴功能衰退和紊乱、下丘脑-垂体-性腺轴功能衰退和紊乱或胸腺功能衰退和紊乱的药物中的应用。
上述小分子化合物SPAM1在制备预防或治疗在延长寿命、预防与治疗随龄的机体衰老、男女更年期综合征、男女性功能随龄衰退、男女生殖功能衰退、免疫功能失调与衰退或脓毒症的药物中的应用。
与现有技术相比，本发明具有如下有益效果：
(1)本发明的SPAM1分子量小，能高效穿越生物学屏障，包括血脑屏障、血睾屏障等；
(2)本发明的SPAM1正反馈上调下丘脑-垂体分泌的神经递质/调质PACAP及其特异受体PAC1-R的表达，作用于性腺轴和肾上腺轴的下游腺体，因此其调控作用是全面的；
(3)本发明的SPAM1特异靶向PAC1-R1，仅作用于天然表达PAC1-R神经系统与内分泌系统的细胞和组织，副作用较小。
因此，SPAM1将成为有效治疗与预防与神经肽PACAP密切相关的，神经系统、内分泌系统及免疫系统功能衰老与紊乱的新型小分子化合药物。
附图说明
图1：小分子SPAM1合成工艺(两步法)；A：2-氨基苯甲酰胺；B：戊二酸酐；C：4-(4-氧-3,4-二氢喹唑啉-2-基)丁酸；D：苯并[d][1,2,3]三唑-1-醇；E：4-(氨甲基)苯甲酸；F：三乙胺。
图2：中间产物C的核磁共振检测；1HNMR(400MHz，DMSO)：12.16(米，2H)，8.08(d，J＝5.8Hz，1H)、7.79-7.76(米，1H)，7.60(d，J＝6.6赫兹，1H)，7.46(d，J＝6.0赫兹，1H)，2.64(t，J＝6.0赫兹，2H)，2.32(t，J＝5.6赫兹，2H)，2.00-1.96(米，2H)。
图3：SPAM1的核磁共振检测；1HNMR(400MHz，DMSO-d6)＝12.79(s，1H)，12.18(s，1H)，8.42(t，J＝6.0Hz，1H)，8.09(d，J＝7.9Hz，1H)，7.90(d，J＝7.9Hz，2H)，7.78(t，J，1H)，7.78(t，J，1H)，J＝7.6Hz，1H)，7.61(d，J＝8.2Hz，1H)，7.47(t，J＝7.5Hz，1H)，7.36(d，J＝7.9Hz，2H)，4.33(d，J＝5.9Hz，2H)，2.64(t，J＝7.4Hz，2H)，2.27(t，J＝7.5Hz，2H，2.09＝1.95(米，2H)。
图4：SPAM1在体上调PACAP的血浆浓度(*,P<0.01,SPAM1+vs.SPAM1-)。
图5：Westernblot检测SPAM1浓度依赖地上调PAC1-R在神经细胞Neuro2a的表达。
图6：免疫荧光检测SPAM1有效上调PAC1-R在神经细胞SHSY-5Y的表达。
图7：酶联免疫法检测腹腔注射SPAM1浓度依赖地上调血清皮质酮水平(*,P<0.01,SPAM1vs.对照组)。
图8：SPAM1有效上调雌二醇和黄体生成素，抵抗D-半乳糖诱导的卵巢衰退(*,P<0.01,衰老模型组vs.正常组；#,P<0.01,SPAM1干预组vs.衰老模型组)。
图9：SPAM1有效上调睾酮，抵抗D-半乳糖诱导的睾丸衰退(*,P<0.01,衰老模型组vs.正常组；#,P<0.01,SPAM1干预组vs.衰老模型组)。
图10：SPAM1有效上调胸腺指数，抵抗地塞米松诱导的胸腺衰退(*,P<0.01,衰老模型组vs.正常组；#,P<0.01,SPAM1干预组vs.衰老模型组)。
图11：SPAM1有效降低LPS诱导脓毒症的死亡率，提高生存率。
具体实施方式
下面结合具体实施例对本发明做进一步地描述，但具体实施例并不对本发明做任何限定。
实施例1：SPAM1的中试合成工艺(两步法)
按图1所示，采用两步法合成。第一步：在装有冷凝器的150mL烧瓶中，苯甲酰胺A(5.45克、40.0毫摩尔、1.0等)和琥珀氢化物B(4.00克、40.0毫摩尔、1.0等)混合在50mL的甲苯中。悬架被大力回流3小时，然后冷却至室温。所得的产物C为白色固体被过滤，用Et2O洗涤并干燥(8.833克，产量88.3％)。产物核磁共振检测如图2所示。
第二步：按下列喂食比进行合成：
| 项目代码 | C | D | E | F | EDCI | DCM |
| 源数(g) | 10.00 | 5.82 | 6.51 | 13.07 | 9.08 | 200mL |
| 摩尔等效物(eq) | 1.0 | 1.0 | 1.0 | 3.0 | 1.1 | 20mL/g |
在室温下，依次向500mL反应瓶中加入C和D，然后加入溶剂DCM和F，搅拌。分批添加收缩剂EDCI，继续对系统进行澄清，颜色为深棕色。将E添加到反应系统中，并继续反应，直到原材料E消失且反应结束。中央控制过程：展开剂DCM/MeOH＝3/1样品1-2滴，用少量MeOH完全溶解1滴薄HCl，点板控制原料E。反应24小时后，反应液直接浓缩去除反应溶剂，得到泥状灰色粗品。所得泥状粗品用DMF/H2O＝1/3(4mL/g，相对于粗品)室温搅拌打浆过夜，然后过滤，滤饼用EtOH/EA＝1/1洗涤至类白色，烘干。结果：得产品6.4g，收率：40.6％，得白色固体粉末为SPAM1。SPAM1的核磁共振测定如图3。
实施例2：SPAM1有效上调机体PACAP的水平
BALb/c小鼠30只，SPF级，周龄8-10周，体重22-27g，雌雄各半，随机分为3组，每组10只：1)SPAM1低剂量组，腹腔注射10umol/kg；2)SPAM1高剂量组，腹腔注射100umol/kg；3)正常对照组，腹腔注射生理盐水；注射后30min，眼眶采血，血清采用ELISA试剂盒进行PACAP检测。结果如图4所示，SPAM1有效上调血清中PACAP的含量，而且上调作用具有浓度依赖性。
实施例3：SPAM1有效上调PACAP特异受体PAC1-R的表达
天然表达PAC1-R的小鼠神经细胞Neuro2a培养至融合率为80％以上，分别加入1uM-100uM的SPAM1，孵育1h后，破碎细胞；全细胞溶解液上清进行SDS-PAGE和应用抗PAC1-R的C端的抗体进行western blot检测。结果如图5所示，1uM、10uM和100uM的SPAM1呈现浓度依赖的方式上调神经细胞中PAC1-R的表达。
天然表达PAC1-R的人神经细胞SHSY-5Y培养至融合率为80％以上，100uM SPAM1孵育1h后，进行免疫荧光共聚焦观察：细胞核DAPI染色呈紫蓝色，而靶向PAC1-R的红色荧光信号被SPAM1显著上调(图6)。
实施例4：SPAM1有效在体上调皮质酮水平
BALb/c小鼠40只，SPF级，周龄8-10周，体重22-27g，雌雄各半，随机分为3组，每组10只：1)SPAM1低剂量组，腹腔注射10umol/kg；2)SPAM1中剂量组，腹腔注射100umol/kg；2)SPAM1高剂量组，腹腔注射1000umol/kg；3)正常对照组，腹腔注射生理盐水；注射1h后，眼眶采血，固相夹心法酶联免疫吸附实验(ELISA)检测血清中COR的水平，结果如图7所示：SPAM1以浓度依赖方式提高血清COR水平，显示SPAM1提高机体的应激能力。
实施例5：SPAM1有效抵抗D-半乳糖诱导的卵巢衰退
采用D-半乳糖诱导的衰老模型，BALb/c雌性小鼠40只，SPF级，周龄8-10周，体重22-27g，随机分为4组，每组10只：1)衰老模型组，颈背部皮下注射D-半乳糖(200mg/kg/d*42d)；2)SPAM1低剂量干预组，如组1)一样注射D-半乳糖，在第15天加入腹腔注射低剂量SPAM1(10umol/kg/d*28d)；3)SPAM1高剂量干预组，如组1)一样注射D-半乳糖，在第15天加入腹腔注射高剂量SPAM1(100umol/kg/d*28d)；4)正常对照组，用生理盐水替代D-半乳糖和SPAM1；在完成所有注射后的24h，眼眶采血，酶联免疫法(ELISA)检测血清中雌二醇和黄体生成素的水平。结果如图8所示：D-半乳糖显著下调雌性小鼠血清中雌二醇和黄体生成素的水平，而低浓度和高浓度的SPAM1均有效上调衰老小鼠血清的雌二醇和黄体生成素的水平，并且高浓度组比低浓度组作用更为显著；结果显示SPAM1有效抵抗卵巢衰退。
实施例6：SPAM1有效抵抗D-半乳糖诱导的睾丸衰退
采用D-半乳糖诱导的衰老模型，BALb/c雄性小鼠40只，SPF级，周龄8-10周，体重22-27g，随机分为4组，每组10只：1)衰老模型组，颈背部皮下注射D-半乳糖(200mg/kg/d*42d)；2)SPAM1低剂量干预组，如组1)一样注射D-半乳糖，在第15天加入腹腔注射低剂量SPAM1(10umol/kg/d*28d)；3)SPAM1高剂量干预组，如组1)一样注射D-半乳糖，在第15天加入腹腔注射高剂量SPAM1(100umol/kg/d*28d)；4)正常对照组，用生理盐水替代D-半乳糖和SPAM1；在完成所有注射后的24h，眼眶采血，酶联免疫法(ELISA)检测血清中睾酮的水平。结果如图9所示：D-半乳糖显著下调雄性小鼠血清中睾酮的水平，而低浓度和高浓度的SPAM1均有效上调衰老小鼠血清的睾酮的水平，并且高浓度组比低浓度组作用更为显著；结果显示SPAM1有效抵抗睾丸的衰退。
实施例7：SPAM1有效抵抗胸腺衰退
采用地塞米松诱导的胸腺衰退模型，BALb/c小鼠40只，SPF级，雌雄对半，周龄8-10周，体重22-27g，随机分为4组，每组10只：1)衰老模型组，腹腔注射地塞米松(25mg/kg/d*2d)；2)SPAM1低剂量干预组，如组1)一样注射地塞米松，同时加入腹腔注射低剂量SPAM1(10umol/kg/d*2d)；3)SPAM1高剂量干预组，如组1)一样注射地塞米松，同时加入腹腔注射高剂量SPAM1(100umol/kg/d*2d)；4)正常对照组，用生理盐水替代地塞米松和SPAM1；在完成最后注射后的24h，称取小鼠体重，颈椎脱臼法处死小鼠，取胸腺称重，计算胸腺指数＝胸腺重量(mg)/体重(g)。结果如图10所示，低浓度和高浓度的SPAM1均有效抑制地塞米松诱导的胸腺指数下调。
实施例8：SPAM1有效降低LPS诱导脓毒症的死亡率
采用LPS诱导脓毒症模型，BALb/c小鼠40只，SPF级，雌雄对半，周龄8-10周，体重22-27g，随机分为4组，每组10只：1)脓毒症模型组，腹腔注射生理盐水，30min后，尾静脉注射15mg/kg LPS；2)SPAM1低剂量干预组，腹腔注射低剂量SPAM1(10umol/kg)，30min后，尾静脉注射15mg/kg LPS；3)SPAM1高剂量干预组，腹腔注射高剂量SPAM1(100umol/kg)，30min后，尾静脉注射15mg/kg LPS；4)正常对照组，腹腔注射生理盐水，30min后，尾静脉注射生理盐水；每隔24h观察小鼠存活情况，记录各组小鼠8d的存活率。结果如图11所示，低浓度和高浓度的SPAM1均有效抑制LPS诱导脓毒症导致的死亡，降低浓度症的死亡率。
Claims (5)
1.上调神经肽PACAP及其受体PAC1-R的小分子化合物SPAM1，其结构如式(Ⅰ)所示，其中R＝无或H20或HCl；
2.权利要求1所述小分子化合物SPAM1的制备方法，其特征是分两步合成，包括如下步骤：
(1)2-氨基苯甲酰胺和戊二酸酐聚合反应获得基础化合物4-(4-氧-3,4-二氢喹唑啉-2-基)丁酸；
(2)4-(4-氧-3,4-二氢喹唑啉-2-基)丁酸再和苯并[d][1,2,3]三唑-1-醇、4-(氨甲基)苯甲酸和三乙胺缩合而成。
3.权利要求1所述小分子化合物SPAM1在制备预防或治疗与神经肽PACAP密切相关的，神经系统、内分泌系统或免疫系统功能衰老与紊乱的药物中的应用。
4.权利要求1所述小分子化合物SPAM1在制备预防或治疗下丘脑-垂体-肾上腺轴功能衰退和紊乱、下丘脑-垂体-性腺轴功能衰退和紊乱或胸腺功能衰退和紊乱的药物中的应用。
5.权利要求1所述小分子化合物SPAM1在制备预防或治疗在延长寿命、预防与治疗随龄的机体衰老、男女更年期综合征、男女性功能随龄衰退、男女生殖功能衰退、免疫功能失调与衰退或脓毒症的药物中的应用。
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| CN109293584A (zh) * | 2018-09-25 | 2019-02-01 | 暨南大学 | 靶向神经肽受体pac1-r的小分子别构调节化合物spam及其制备方法和用途 |
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| CN109293584A (zh) * | 2018-09-25 | 2019-02-01 | 暨南大学 | 靶向神经肽受体pac1-r的小分子别构调节化合物spam及其制备方法和用途 |
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| C. O. USIFOH: "3-Propynyl-2-substituted carboxylic acid derivatives of quinazolinone", 《SCI. PHARM.》 * |
| XIAOLING HUANG ET AL.: "Hormesis effect of hydrogen peroxide on the promoter activity of neuropeptide receptor PAC1‐R", 《JOURNAL OF BIOCHEMISTRY》 * |
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