CN106102742A - 利用细胞外钙调节针对代谢型谷氨酸受体的药物作用 - Google Patents
利用细胞外钙调节针对代谢型谷氨酸受体的药物作用 Download PDFInfo
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Abstract
本发明公开了通过增加或降低细胞外Ca2+的水平来调节正构或变构药物对I组代谢型谷氨酸受体(mGluR)的活性的方法。
Description
相关申请的交叉引用
本申请案要求2013年9月13日提交的第61/877,579号美国临时申请案和2013年11月26日提交的第61/909,134号美国临时申请案的权益,所述临时申请案的全部内容都以引用方式并入本文。
背景
代谢型谷氨酸受体(mGluR)的八个亚型属于C家族G蛋白偶联受体(GPCR)并且拥有一个大胞外结构域(ECD)、七个跨膜结构域(TMD)和胞质C端尾部。mGluR广泛表达于中枢神经系统中并且在于兴奋性和抑制性突触中调节神经元兴奋性和突触可塑性方面起关键作用(Neyman,S.等人(2008)The European journal of neuroscience 27:1345-1352)。广泛的结构研究已经揭示,内源性激动剂L-谷氨酸(L-Glu)(中枢神经系统中的主要兴奋性神经递质)在受体的Venus Fly Trap(VFT)基序内的ECD的铰链区结合以激活蛋白质。这随后刺激磷脂酶C(PLC)并导致三磷酸肌醇(IP3)的累积和细胞内钙浓度([Ca2+]i)的增加(Lavreysen,H.等人(2003)Molecular pharmacology63:1082-1093;Lindsley,C.W.等人(2004)Journal of medicinal chemistry47:5825-5828;Kubo,Y.等人(1998)Science279:1722-1725)。
近年来,mGluR作为用于治疗一系列精神和神经疾病的潜在药物靶标已受到越来越多的关注(Whang,P.G.等人(2008)Orthopedics 31(10))(图1)。靶向mGluR的配体可以被分类为正构激动剂和拮抗剂以及变构调节剂。正构激动剂和拮抗剂通过竞争性结合至L-Glu结合口袋分别诱导和减弱受体的活性。L-使君子氨酸(L-Quis)是迄今为止所报道的最有效的mGluR1激动剂(Yuan,K.等人(2011)J Biol Chem 286:24776-24784;Chen,Y.等人(2011)The Biochemical journal 435:711-722),其已被推测为与L-Glu共有几乎相同的结合口袋(Levant,J.A.等人(1973)The New England journal of medicine289:555-558;Sato,T.等人(2003)J Biol Chem 278:4314-4321)。相反地,(S)-α-甲基-4-羧基苯基甘氨酸(“(s)-MCPG”)是L-Glu的类似物和非选择性竞争性拮抗剂,其已被证明占据L-Glu结合口袋,从而阻断mGluR家族的I/II组成员的功能(Tsuchiya,D.等人(2002)Proc Natl AcadSci USA.99:2660-2665)。另一方面,变构调节剂与正构中心以外的位点结合,从而影响受体的活性。分子(9H-呫吨-9-羰基)氨基甲酸丁酯(“Ro 67-4853”)是通过与受体的TMD相互作用来增强L-Glu的效力的mGluR1正向变构调节剂(PAM)。分子(7E)-7-羟基亚氨基-1,7a-二氢环丙烷并[b]色烯-1a-羧酸(-)-乙酯(“CPCCOEt”)是负向变构调节剂(NAM),其通过特异性结合至位于mGluR1α的第三胞外环中的位点来抑制mGluR1被L-Glu激活(Nagar,B.等人(1996)Nature 380:360-364)。
发明概要
公开了通过增加或降低细胞外Ca2+来调节正构或变构药物对I组代谢型谷氨酸受体(mGluR)(例如mGluR1、mGluR5或其组合)的活性的方法。所述正构或变构药物可以是激动剂、拮抗剂或变构调节剂。还公开了一种用于治疗受试者中的完全或部分由I组mGluR介导的疾病或病症的方法。
I组mGluR的选择性药理拮抗剂和/或负向变构调节剂是用于治疗中枢神经系统(CNS)的众多病症的潜在治疗剂,这些病症包括抑郁症、焦虑症、药物成瘾、慢性疼痛、脆性X染色体综合症(FXS)、自闭症谱系障碍(ASD)、帕金森氏病(Parkinson’s disease)和胃食管返流病。此外,I组mGluR的激动剂和正向变构调节剂(PAM)是用于治疗其它CNS病症的潜在治疗剂,这些病症包括精神分裂症、与长期吸毒有关的认知缺陷和消退性学习中的缺陷。因此,这些活性可以通过增加细胞外Ca2+来增强。
所述方法可以涉及向受试者施用一种或多种I组mGluR的正构激动剂、正构拮抗剂或变构调节剂(例如表1A或1B中所陈述的那些)。所述方法可以进一步涉及向受试者施用调节正构激动剂、正构拮抗剂或变构调节剂的活性的量的用于增加或降低细胞外Ca2+水平的钙剂。因此,在一些实施方案中,正构激动剂、正构拮抗剂或变构调节剂如果与钙剂一起施用则可以以低于其正常有效剂量(ED)的剂量来施用。例如,正构激动剂、正构拮抗剂或变构调节剂可以以比其正常ED50低至少10%、20%、30%、40%、50%、60%、70%、80%或90%的量来施用。
在公开的方法的一些方面,正构激动剂、正构拮抗剂或变构调节剂与钙剂一起以单一剂量单位配制。因此,还公开了一种组合物,其包含一种或多种mGluR的正构激动剂、正构拮抗剂或变构调节剂(在本文中统称为“mGluR正构或变构药物”)与钙剂的组合。这种组合物可以包含足以提供促进或抑制mGluR活性的有效剂量的量和比率的mGluR正构或变构药物和钙剂。应当了解,组合物中的钙剂的量可以影响对于有效剂量而言所需要的mGluR正构或变构药物的量。因此,最佳的量和比率可以针对每种组合和预期用途凭经验来确定。
在一些实施方案中,钙剂是食品或钙补充剂。在一些实施方案中,钙剂是影响mGluR对钙的敏感性的神经递质或氨基酸。在一些实施方案中,钙剂是促进从细胞钙库的钙释放的神经递质。在一些实施方案中,钙剂是电或机械刺激。
附图和以下描述陈述了本发明的一个或多个实施方案的细节。根据具体实施方式和附图以及权利要求书,本发明的其它特征、目的和优点将变得显而易见。
附图说明
图1A和1B是mGluR1αECD中的[Ca2+]o、L-Glu、L-Quis和(s)-MCPG的结合位点的示意图。图1A示出了[Ca2+]o结合位点在I组mGluR和T1R3中高度保守。相反地,虽然序列比对表明[Ca2+]o结合位点在I组mGluR中高度保守,但它在亚族的其它成员中不保守。图1B示出了L-Glu、L-Quis和(s)-MCPG结合口袋(菱形)以及作用于mGluR1α的各种配体的结合位点的示意图。类似于L-Glu结合口袋,Y74、R78、S165、T188、Y236、D318和K409形成L-Quis结合口袋。有助于形成L-Glu结合口袋的类似残基Y74、W110、S165、T188、Y236、D318和K409也参与(s)-MCPG的结合。L-Glu、L-Quis和(s)-MCPG楔入与ECD中的[Ca2+]o结合位点相邻的位置并且使受体的结构分别保持其活性和休眠形式。具有多于一条虚线的残基指示那些具有多于一个有助于配体结合的氧原子的残基。已发现大多数正向(三角形)和负向(五角形)变构调节剂结合至TMD,但不共有相同的结合位点。
图2是WT mGluR1α以及D318I、D322I和E325I的相关图。预测的[Ca2+]o结合位点与L-Glu结合口袋十分相关。[Ca2+]o结合位点的突变损害与L-Glu结合口袋的相关性。对应于x轴的[Ca2+]o结合位点由长方形突出。
图3A至3E显示细胞外Ca2+通过结合至预测的[Ca2+]o结合位点增强mGluR1α的L-Quis活化。(A-C)添加1.8mM[Ca2+]o(实点)增加由mGluR1α活化介导的L-Quis诱导的[Ca2+]i反应。在0mM[Ca2+]o下的反应由空心圆圈指示。在1.8mM[Ca2+]o的存在下,D322I的L-Quis敏感性增加。1.8mM[Ca2+]o还增强L-Quis对E325I的效力。(D)在使[Ca2+]o从标称零值增加至1.8mM后,针对L-Quis激活WT mGluR1α、D322I和E325I的EC50的倍数变化。WT mGluR1α、D322I和E325I的EC50值的降低倍数分别为4.6、3.9和2.7。(E)[3H]-L-Quis在没有[Ca2+]o的情况下结合至WT mGluR1α,但[Ca2+]o结合位点中的突变减少L-Quis结合。D318I消除L-Quis结合,而D322I和E325I仍然保留L-Quis结合。添加5mM[Ca2+]o增强L-Quis与WT mGluR1α(p=0.031)和D322I的结合,而这种[Ca2+]o效应在E325I中被消除。所用的结合缓冲液是低渗缓冲液(N=3)。(*p<0.05)
图4A至4C显示(s)-MCPG对WT mGluR1α对L-Glu和[Ca2+]o的反应的影响。(A)在5μML-Glu的存在下增加(s)-MCPG的浓度抑制mGluR1α,且1.5mM(s)-MCPG完全阻断L-Glu对受体的活化。(s)-MCPG减弱mGluR1α对5mM[Ca2+]o的反应,且2.0mM MCPG不完全抑制受体感受[Ca2+]o的能力。(B)0.5mM(s)-MCPG竞争性抑制L-Glu诱导的[Ca2+]i反应。Lineweaver-Burk曲线图分析表明(s)-MCPG与L-Glu竞争(插图)。(C)0.5mM(s)-MCPG抑制低[Ca2+]o诱导的[Ca2+]I反应,但高[Ca2+]o恢复受体的反应(N=3)。
图5A至5B显示CPCCOEt对mGluR1α对L-Glu和[Ca2+]o的反应的影响。(A)在10或40μMCPCCOEt的存在下,mGluR1α对L-Glu的敏感性降低。在40μM CPCCOEt的存在下,最大反应减少至约50%。(B)添加5或40μM CPCCOEt降低了野生型mGluR1α的[Ca2+]o敏感性。在不存在(实心圆点)或存在5μM(实心方形)或40μM(空心圆圈)CPCCOEt的情况下利用Fura-2AM测量[Ca2+]i。在受CPCCOEt(5或40μM)抑制的细胞中,增加[Ca2+]o抵消CPCCOEt的抑制作用。将瞬时表达WT mGluR1α的HEK293细胞固定在盖玻片上,并收集由fura-2AM指示的[Ca2+]i变化(N=3)。
图6A至6C显示[Ca2+]o和Ro 67-4853共激活mGluR1α。在盖玻片上生长的HEK293细胞被野生型mGluR1α瞬时转染。加载染料后,在10mM HEPES、140mM NaCl、5mM KCl、0.55mMMgCl2、0.5mM CaCl2和5nM Ro 67-4853(pH 7.4)中预孵育细胞10min。(A)10或100nM Ro 67-4853增强mGluR1α的L-Glu敏感性。(B)30或300nM Ro 67-4853提高mGluR1α的[Ca2+]o敏感性(C)将[Ca2+]o和Ro 67-4853添加到细胞中。Ro 67-4853在0.5mM[Ca2+]o的存在下展现对mGluR1α的活性,而1.8mM[Ca2+]o增强其效力。
图7A和图7B显示E325I在L-Glu的存在下保留受体对10μM Ro 67-4853的增强的反应性,但失去了[Ca2+]o对它的增强作用。(A)在1.8mM[Ca2+]o的存在下,添加30μM L-Glu增加E325I的Ro 67-4853敏感性(P=0.014)。(B)E325I在没有[Ca2+]o和L-Glu的情况下对10μMRo 67-4853反应。使[Ca2+]o从0增加至5.0mM不对E325I对Ro 67-4853的反应产生影响,而WTmGluR1对Ro 67-4853的活性逐渐增强至E325I的[Ca2+]i反应增加(N=3)(*p<0.05)。WTmGluR1和E325I当在5mM Ca2+的存在下分别暴露于10μM和20μM Ro 67-4853时均具有更强的反应(*P<0.05)。
图8示出了细胞外Ca2+浓度变化诱导细胞内Ca2+振荡。细胞外Ca2+浓度从0.05mM增加至1.8mM。在不同的Ca2+浓度之间使用不含Ca2-的槽液以移除先前的添加。
图9A至9C显示不同的细胞外Ca2+浓度导致不同频率的细胞内Ca2+振荡。
图10是显示更高的细胞外Ca2+浓度引发过度表达mGluR5的HEK293细胞中的更快细胞内Ca2+振荡的条形图。
图11A至11C示出了在0.0mM(图11A)、0.5mM(图11B)和1.8mM(图11C)细胞外Ca2+的存在下mGluR对L-Glu的反应。在没有Ca2+的情况下,需要更高剂量的L-Glu来活化mGluR5,而如果施加细胞外Ca2+,则较低的L-Glu就可以活化mGluR5。
图12是显示在不同细胞外Ca2+的存在下具有作为对L-Glu的反应的振荡的细胞的百分比的条形图。在没有细胞外Ca2+的情况下,低浓度的L-Glu只能够引发极少数的细胞振荡(小于10%),而如果存在0.5或1.8mM Ca2+,超过50%的细胞开始振荡。
图13A至13D是显示用含有0、0.5或1.8mM Ca2+和1μM(图13A)、3μM(图13B)、5μM(图13C)或10μM(图13D)被添加来激活mGluR5的L-Glu的槽液孵育的细胞的细胞内Ca2+振荡频率的条形图。当施加相同浓度的L-Glu时,更多在具有更高Ca2+的槽液中孵育的细胞可以在更高的频率下振荡。
图14A至14B示出了在不存在或存在细胞外Ca2+的情况下Ro-674853对mGluR5的刺激作用。当没有在槽液中施加Ca2+时(图14A),Ro-674853(从5nM至100nM)不能刺激mGluR5,而在0.5mM Ca2+的存在下(图14B),5nM Ro-674853导致高频率Ca2+振荡,这表明mGluR5被活化。
图15A至15C示出了细胞外Ca2+对由L-Quis引发的mGluR5反应的影响。存在于0mMCa2+槽液中的细胞几乎不显示任何对L-Quis的反应(图15A),而置于0.5mM(图15B)或1.8mM(图15C)Ca2+槽液中的细胞对添加L-Quis展现立即和强烈的反应。细胞外Ca2+浓度越高,振荡频率就越高。
图16A显示当将细胞放置在更高的细胞外Ca2+槽液中时,相同浓度的L-Quis引发更快的细胞内Ca2+振荡。图16B示出了从左(较低振荡频率)向右(较高振荡频率)转换的细胞振荡频率。图中的箭头指出了转换方向。
图17是显示具有L-Quis引发的反应的细胞的百分比的条形图。在没有添加细胞外Ca2+的情况下,需要较高的L-Quis浓度来引发细胞反应(小于20%),而在添加细胞外Ca2+的情况下,5nM L-Quis已经引发超过60%的细胞展现细胞内Ca2+变化。
图18显示细胞外钙可以增强受mGluR1转染的HEK293细胞中的谷氨酸诱导的细胞内钙释放。使用含有1.7uM谷氨酸/3mM钙/1.7uM谷氨酸和3mM钙的林格缓冲液(Ringerbuffer)处理细胞,以研究mGluR1功能。
图19显示细胞外钙可以增强受mGluR1转染的HEK293细胞中的谷氨酸诱导的细胞内钙释放。使用含有17uM谷氨酸/6mM钙/17uM谷氨酸和6mM钙的林格缓冲液处理细胞,以研究mGluR1功能。
图20显示1.7uM谷氨酸和3mM细胞外钙在一起可以引发细胞内钙振荡。
图21显示17uM谷氨酸和6mM细胞外钙在一起引发细胞内钙振荡。
图22是mGluR1、mGluR2、mGluR3、mGluR4、mGluR5、mGluR6、mGluR7和mGluR8的蛋白质序列比对。着重标出的斜体残基是每种mGluR的谷氨酸结合位点。加粗的残基是mGluR1中的钙结合位点1(D318、D322和D325)。加粗和加下划线的是钙结合位点2(L86-G102)。仅有下划线的部分是钙结合位点3(S129、G144)。用于mGluR比对的物种来自大鼠且所有序列产生自Uniprot。
具体实施方式
与C GPCR家族的其它成员例如钙敏感受体(CaSR)一样,mGluR1α使用胞外结构域来感受[Ca2+]o(Huang,Y.等人(2009)Biochemistry 48:388-398;Huang,Y.等人(2007)JBiol Chem 282:19000-19010)。mGluR1介导的Ca2+活化Cl-通道的激活除L-Glu以外还受[Ca2+]o的调节(Kubo,Y.等人(1998)Science279:1722-1725)。来自mGluR1敲除小鼠的Purkinje细胞失去了对[Ca2+]o的敏感性,而这种对[Ca2+]o的敏感性在mGluR1通过基因方式重新引入小鼠中后被恢复(Tabata,T.等人(2002)Mol Cell Neurosci 20:56-68)。关于[Ca2+]o影响各种类别的化合物对mGluR的作用有零星的报道(Suzuki,Y.等人(2004)J BiolChem 279:35526-35534)。然而,还不清楚[Ca2+]o如何能够调节mGluR1的活性或各种mGluR1配体的作用,并且迄今为止还没有在通过X射线晶体学解析的15种结构中鉴定出Ca2+结合位点。
利用最近开发的计算算法,在mGluR1α的ECD的铰链区内鉴定出[Ca2+]o结合位点,其与报道的L-Glu结合位点相邻(Wang,X.等人(2009)Proteins75:787-798;Wang,X.等人(2010)Protein science:a publication of the Protein Society 19:1180-1190)。其由D318、E325、D322和天然激动剂的羧酸侧链L-Glu组成。L-Glu和D318的羧酸侧链均参与L-Glu结合和[Ca2+]o结合。诱变研究表明,L-Glu与Ca2+结合至它们的不同但部分重叠的结合位点协同地调节mGluR1α介导的细胞内Ca2+([Ca2]i信号传导的激活。使L-Glu结合位点突变完全消除了L-Glu信号传导,而其Ca2+感受能力在很大程度上是完整的。使预测的Ca2+结合残基突变不仅消除或显著降低mGluR1α对[Ca2+]o的敏感性,而且在一些情况下,还消除或显著降低对L-Glu的敏感性(Jiang,Y.等人(2010)J Biol Chem 285:33463-33474)。
调查了[Ca2+]o对作用于mGluR1α的不同正构配体(包括L-Quis、(s)-MCPG)的作用的调节作用,以及Ca2+与mGluR1变构调节剂Ro 67-4853和CPCCOEt之间的双向相互作用。发现预测的Ca2+结合位点与正构激动剂和拮抗剂相互作用位点相邻,并且如通过分子动力学(MD)模拟所评估,展现出与这些位点的良好的动态相关运动。这些研究另外表明,[Ca2+]o增强[3H]-L-Quis与野生型mGluR1α的结合并且一致地诱导[Ca2+]i。此外,这些研究表明,(s)-MCPG在低浓度下有效地拮抗由L-Glu和[Ca2+]o诱导的受体活化,但增加L-Glu或[Ca2+]o的浓度可以克服这种抑制。另外,这些研究表明,Ro-674853和CPCCOEt分别增强和抑制对[Ca2+]o的反应,且[Ca2+]o提高Ro-674853的效力,但减少CPCCOEt对mGluR1α的抑制。因此,[Ca2+]o可能通过与受体的ECD中的预测的[Ca2+]o结合位点相互作用来调节mGluR1α对正构激动剂和拮抗剂以及变构调节剂的敏感性。
因此,如本文所公开,在I组mGluR的铰链区内存在Ca2+结合位点,其与正构激动剂和拮抗剂药物在受体的胞外结构域上结合的位点相邻。此外,细胞外Ca2+增强由正构激动剂引起的I组mGluR介导的细胞内Ca2+反应,并降低mGluR正构拮抗剂的抑制作用。另外,mGluR的选择性正向和负向变构调节剂分别增强和抑制对细胞外Ca2+的反应。因此,细胞外Ca2+与mGluR的ECD中的预测Ca2+结合位点的结合不仅调节谷氨酸引起的信号传导,而且调节正构和变构药物对mGluR的作用。
正构和变构mGluR调节剂
迄今为止,已经克隆和表征了八种不同的mGluR受体亚型,且这些受体似乎具有不同的神经解剖学分布以及独特的药理和细胞内信号传导性质。mGluR的I组家族由mGluR1和mGluR5受体组成,而II组家族由mGluR2和mGluR3组成,且III组家族由mGluR4、mGluR6、mGluR7和mGluR8组成。所公开的方法和组合物可以涉及使用在I组mGluR的L-Glu结合口袋中结合的mGluR的任何正构激动剂或拮抗剂。
所述方法和组合物还可以与影响L-Glu与I组mGluR的结合的任何变构调节剂一起使用。mGluR1和mGluR5的激动剂、拮抗剂和变构调节剂的实例陈述于表1A和表1B中。
细胞外钙调节剂
公开的组合物和方法可以涉及使用可以调节I组mGluR受体附近的细胞外钙水平的任何试剂、方案、系统或方法。具体来说,所述组合物和方法涉及调节中枢或周围神经系统(例如大脑)中的细胞外钙水平的钙剂。
在一些实施方案中,钙水平比当前水平提高至少5%、10%、15%、20%、25%、30%、40%、45%、50%、55%、60%、65%、70%、75%、80%、90%、100%、200%或300%。在一些实施方案中,钙水平降低至少5%、10%、15%、20%、25%、30%、40%、45%、50%、55%、60%、65%、70%、75%、80%或90%。
钙补充剂
公开的钙剂可以是能够在受试者的血浆中将血浆中的游离离子钙浓度提高到至少1.0mmol/L(2.0mEq/L)的任何来源的钙。钙(Ca2+)必须以可溶形式存在,以便从胃肠道有效吸收。这种可溶形式通常为Ca2+离子,其被溶剂水水合或与溶液中的阴离子配体松散地复合。从胃肠道进行钙吸收通过主动运输和被动扩散发生。主动运输是可饱和的,受1,25-二羟基维生素D3刺激,且在十二指肠和空肠近端中占主导;而被动运输是用于吸收大负载的Ca2+(其使主动过程饱和)的主要机制,且涉及具有较长运输时间的空肠远端和回肠。
许多关于Ca2+吸收的研究已经采用250mg至2000mg的单口服剂量。在较小的剂量(15-500mg Ca2+)下,吸收分数的变化与负载大小的对数成反比。在较大的负载(>500mg至2000mg)下,吸收分数随着负载大小线性增加,这反映出被动运输的作用超过主动运输。还已经通过将吸收量拟合至具有针对饱和过程的双曲线项和针对不饱和过程的线性项的方程来建立钙吸收的模型。
在一些实施方案中,钙剂可以包括元素钙、钙盐和复合钙补充剂。在各个实施方案中,钙增加剂是钙盐。在一些实施方案中,钙增加剂可以是元素钙或钙盐或复合钙,其在单次施用剂量和/或几小时至几天、几天至几周或几周至几月的时间段内的多次施用剂量后将受试者中的游离离子钙的血浆浓度提高到至少1.0mmol/L(2.0mEq/L)。
一旦已知总血浆钙浓度,就容易计算出游离离子钙。总血浆钙浓度由三个部分组成。约15%结合至多种有机和无机阴离子,例如硫酸根、磷酸根、乳酸根和柠檬酸根。约40%以0.8mg/DI(0.2mmol/L或0.4mEq/L)钙/1.0g/DI(10g/L)白蛋白的比率结合至白蛋白。剩余的45%作为生理活性的离子(或游离)钙循环。离子钙浓度受甲状旁腺激素和维生素D严格调控。正常总血浆钙浓度的广泛范围可能是由于正常健康个体间的血浆白蛋白浓度的变化以及由于水合状态和动脉酸碱平衡的变化或受试者中增加的乳酸盐、柠檬酸盐等的血液浓度可以改变白蛋白浓度和因此改变游离离子钙水平。净效应为仅测量总血浆钙浓度可能有误导性,因为这些参数可以改变,从而影响离子钙分数。
在一些实施方案中,钙剂可以包括钙补充剂。公开的组合物还可以用一种或多种钙补充剂通过以下方式来配制,在组合物中提供足够的钙补充剂以使组合物中的预定元素钙量达到例如约100mg至约5000mg、100mg至约2000mg、约500mg至约1,000mg。
神经递质或氨基酸
在一些实施方案中,钙剂是影响mGluR对钙的敏感性的神经递质或氨基酸。在一些实施方案中,钙剂是促进从细胞钙库的钙释放的神经递质。例如,L-谷氨酸是可以与mGluR结合以引发IP3的增加的神经递质。IP3进一步导致CA2+从内质网(ER)的释放。
电或机械刺激
在一些实施方案中,钙剂是电或机械刺激。神经元的电或机械刺激导致细胞外钙经由质膜中的通道(例如,电压门控钙通道、配体门控钙通道)进入细胞。这可以使平均胞质钙浓度从约100nM增加至约1uM。
钙感受
用于测量细胞外钙水平的方法和生物传感器是已知的,并且描述于例如Yang等人的WO 2012/054648和Yang等人的WO 2008/076365中,所述文献以引用的方式整体并入本文中供这些教导用。因此,在一些实施方案中,公开的方法进一步涉及测量细胞外Ca2+水平和如上所述将细胞外Ca2+水平调节至适于增强一种或多种I组mGluR正构激动剂、正构拮抗剂或变构调节剂的活性的最佳水平。大脑中钙的正常细胞外浓度在1.5-2.0mM的范围内(Jones,H.C.和R.F.Keep.1987.J.Physiol.(Lond.).383:441-453)。在一些实施方案中,细胞外Ca2+的“最佳水平”包括比生理水平高至少10%、20%、30%、40%、50%、60%、70%、80%、90%、100%或200%的水平。在特定实施方案中,细胞外Ca2+的“最佳水平”包括比生理水平高至少50%的水平。
治疗方法
所公开的组合物和方法可以用于治疗或预防涉及功能失调的I组代谢型谷氨酸受体活性的任何疾病或病症。代谢型谷氨酸受体已牵涉到一系列生物功能。这已经表明这些受体在人或其它物种的多种疾病过程中的潜在作用。
例如,公开的组合物和方法可以用于治疗或预防与谷氨酸功能失调有关的各种神经和精神病症,包括下列病状或疾病中的一种或多种:认知障碍,包括痴呆(与阿尔茨海默氏病(Alzheimer's disease)、缺血、创伤、血管问题或中风、HIV疾病、帕金森病(Parkinson's disease)、亨廷顿氏舞蹈症(Huntington's disease)、皮克氏病(Pick'sdisease)、克雅二氏病(Creutzfeldt-Jacob disease)、围产期缺氧、其它一般医学病状或物质滥用相关);谵妄、遗忘障碍和年龄相关性认知下降;焦虑症,包括急性应激障碍、广场恐怖症、广泛性焦虑症、强迫症、惊恐发作、恐慌症、创伤后应激障碍、分离焦虑症、社交恐惧症、特定恐惧症、物质诱导型焦虑症和由一般医学病状引起的焦虑症;精神分裂症或精神病,包括精神分裂症(偏执狂样的、紊乱的、紧张症的或未分化的)、精神分裂症样的障碍、情感分裂性精神障碍、妄想性障碍、短时精神障碍、共有型精神障碍、由于一般医学病状导致的精神障碍和由物质诱导的精神障碍;物质相关性障碍和成瘾行为(包括物质诱导的谵妄、持续性痴呆、持续性遗忘症、精神障碍或焦虑症;对包括酒精、安非他命、大麻、可卡因、迷幻剂、吸入剂、烟碱、阿片类药物、苯环利定、镇静药、安眠药或抗焦虑剂的物质的耐受、依赖或戒除);运动障碍,包括运动不能和运动不能强直综合症(包括帕金森病、药物诱导的帕金森症、脑炎后帕金森症、进行性核上性麻痹、多系统性萎缩症、皮质基底核退化症、帕金森症-ALS痴呆复合病和基底神经节钙化)、药物诱导的帕金森症(例如神经安定剂诱导的帕金森症、神经安定剂恶性综合症、神经安定剂诱导的急性肌张力障碍、神经安定剂诱导的急性静坐不能、神经安定剂诱导的迟发性运动障碍和药物诱导的体位性震颤)、抽动秽语综合症(Gilles de la Tourette's syndrome)、癫痫症和运动障碍包括震颤(例如休息性震颤、姿势性震颤和意向性震颤)、舞蹈病(例如西登哈姆氏舞蹈病(Sydenham’s chorea)、亨廷顿氏舞蹈症、良性遗传性舞蹈病、神经棘红细胞增多症、症状性舞蹈病、药物诱导的舞蹈病和偏侧颤搐)、肌阵挛(包括全身性肌阵挛和局灶性肌阵挛)、抽搐(包括单一抽搐、复杂抽搐和症状性抽搐)和肌张力障碍(包括全身性肌张力障碍例如特发性肌张力障碍、药物诱导的肌张力障碍、症状性肌张力障碍和发作性肌张力障碍,以及局灶性肌张力障碍例如眼睑痉挛、口下颌骨肌张力障碍、痉挛性发音困难、痉挛性斜颈、轴向肌张力障碍、张力障碍性书写痉挛和偏瘫性肌张力障碍);肥胖、神经性贪食症和强迫性进食障碍;疼痛,包括骨关节疼痛(骨关节炎)、重复运动疼痛、牙痛、癌痛、肌筋膜疼痛(肌肉损伤、纤维肌痛)、围手术期疼痛(普通外科性、妇科性)、慢性疼痛、神经性疼痛、创伤后疼痛、三叉神经痛、偏头痛和偏头痛性头痛;与过多的食物摄入相关的肥胖或进食障碍及其相关并发症;注意力缺陷/多动障碍;品行障碍;情绪障碍,包括抑郁症、双相性情感障碍、由于一般医学病状所致的情绪障碍和物质诱导的情绪障碍;肌肉痉挛和与肌肉痉挛状态或虚弱相关的障碍,包括震颤;尿失禁;肌萎缩性侧索硬化症;神经元损伤,包括眼损伤、视网膜病变或眼部黄斑变性、听力减退或耳鸣;呕吐、脑水肿和睡眠障碍,包括嗜眠病。神经性疼痛的说明性实例包括糖尿病性多神经病、嵌压性神经病、幻痛、中风后丘脑痛、疱疹后神经痛、拔牙后的非典型面部神经痛疼痛等、脊髓损伤、三叉神经痛和对麻醉止痛药例如吗啡有耐性的癌痛。神经性疼痛包括由中枢或周围神经损伤所引起的疼痛。并且,其包括由单神经病或多神经病造成的疼痛。
具体来说,I组mGluR的选择性药理拮抗剂和/或负向变构调节剂是用于治疗中枢神经系统(CNS)的众多病症的潜在治疗剂,这些病症包括抑郁症、焦虑症、药物成瘾、慢性疼痛、脆性X染色体综合症(FXS)、自闭症谱系障碍(ASD)、帕金森氏病(Parkinson’s disease)和胃食管返流病。此外,I组mGluR的激动剂和正向变构调节剂(PAM)是用于治疗其它CNS病症的潜在治疗剂,这些病症包括精神分裂症、与长期吸毒有关的认知缺陷和消退性学习中的缺陷。因此,这些活性可以通过增加细胞外Ca2+的水平来增强。
组合
公开的正构拮抗剂、正构激动剂或变构调节剂与钙剂的组合可以进一步与一种或多种其它治疗剂组合使用。这类其它药剂可以以其所常用的途径和量与公开的组合物同时或依序施用。当公开的组合物与一种或多种其它药物同时使用时,呈含有这类其它药物和公开的组合物的单位剂型的药物组合物是优选的。然而,组合疗法还可以包括其中公开的组合物和一种或多种其它药物以不同的重叠时间表来施用的疗法。还预期了当与一种或多种其它活性成分组合使用时,公开的组合物和其它活性成分的使用剂量可以低于其在各自单独使用时的剂量。因此,公开的药物组合物包括除与钙剂的组合的正构拮抗剂、正构激动剂或变构调节剂以外还含有一种或多种其它活性成分的那些。
适合与公开的组合物组合的治疗剂为本领域技术人员所熟知,且可以通过查看尤其是医师案头参考(Physician's Desk Reference)(Medical Economics Company,Montvale,N.J.)和默克索引(The Merck Index)(Merck and Co.,Inc.,WhitehouseStation,N.J.)来鉴定。
在一些实施方案中,公开的组合物可以与抗阿尔茨海默氏病药剂、β-分泌酶抑制剂、γ-分泌酶抑制剂、HMG-CoA还原酶抑制剂、NSAID(包括布洛芬、维生素E和抗淀粉样抗体)组合使用。
在一些实施方案中,公开的组合物可以与下列物质组合使用:镇静剂、安眠药、抗焦虑药、抗精神病药、抗焦虑剂、环吡咯酮、咪唑并吡啶、吡唑并嘧啶、弱安定剂、褪黑激素激动剂和拮抗剂、褪黑激素能药、苯并二氮卓类、巴比妥酸盐、5HT-2拮抗剂等,例如:阿地唑仑、阿洛巴比妥、阿洛米酮、阿普唑仑、阿米替林、异戊巴比妥、阿莫沙平、苯他西泮、苯佐他明、溴替唑仑、安非他酮、丁螺环酮、仲丁比妥、布他比妥、卡普脲、卡波氯醛、氯醛甜菜碱、水合氯醛、利眠宁、氯米帕明、氯硝西泮、氯哌唑酮、氯拉卓酸(clorazepate)、氯乙双酯、氯氮平、环丙西泮、地昔帕明、代克拉莫(dexclamol)、地西泮、氯醛比林、双丙戊酸、苯海拉明、多塞平、艾司唑仑、乙氯维诺、依托咪酯、非诺班、氟硝安定、氟西泮、氟伏沙明、氟西汀、磷定安、格鲁米特、哈拉西泮、羟嗪、丙咪嗪、锂、劳拉西泮、氯甲西泮、马普替林、氯安眠酮、褪黑激素、甲苯巴比妥、安宁、甲苯喹唑酮、咪达氟、咪达唑仑、奈法唑酮、尼索氨酯、硝基安定、去甲替林、奥沙西泮、仲醛、帕罗西汀、戊巴比妥、哌拉平、奋乃静、苯乙肼、苯巴比妥、普拉西泮、普鲁米近、丙泊酚、普罗替林、夸西泮、瑞氯西泮、洛利米特、司可巴比妥、舍曲林、舒普罗酮、替马西泮、硫利达嗪、曲卡唑酯、反苯环丙胺、曲唑酮、三唑仑、曲匹泮、三甲氧苯醋酰胺、三氯福司、三氟拉嗪、曲美托嗪、曲米帕明、乌达西泮、文拉法辛、扎来普隆、唑拉西泮、唑吡坦和其盐和其组合等,或主题化合物可以与使用物理方法例如光疗法或电刺激结合施用。
在一些实施方案中,公开的组合物可以与下列物质组合使用:左旋多巴(有或没有选择性脑外脱羧酶抑制剂,例如卡比多巴或苄丝肼);抗胆碱能药,例如比哌立登(任选以其盐酸盐或乳酸盐形式)和三己芬迪(苯海索)盐酸盐;COMT抑制剂例如恩他卡朋(entacapone);MOA-B抑制剂、抗氧化剂、A2a腺苷受体拮抗剂、胆碱能激动剂、NMDA受体拮抗剂、血清素受体拮抗剂和多巴胺受体激动剂例如阿仑替莫、溴隐亭、非诺多泮、麦角乙脲、那高利特、培高利特和普拉克索。应该了解的是,多巴胺激动剂可以呈药学上可接受的盐形式,例如,阿仑替莫氢溴酸盐、溴隐亭甲磺酸盐、非诺多泮甲磺酸盐、那高利特盐酸盐和培高利特甲磺酸盐。麦角乙脲和普拉克索通常以非盐形式来使用。
在一些实施方案中,公开的组合物可以与下列物质组合使用:醋奋乃静、阿仑替莫、苯海索、溴隐亭、比哌立登、氯丙嗪、氯普噻吨、氯氮平、地西泮、非诺多泮、氟奋乃静、氟哌啶醇、左旋多巴、伴有苄丝肼的左旋多巴、伴有卡比多巴的左旋多巴、麦角乙脲、克塞平、甲砜达嗪、莫林酮(molindolone)、那高利特、奥氮平、培高利特、奋乃静、派迷清、普拉克索、利培酮、舒必利、四苯喹嗪、三己芬迪、硫利达嗪、氨砜噻吨或三氟拉嗪。
在一些实施方案中,公开的组合物可以与选自下列物质的化合物组合使用:吩噻嗪、噻吨、杂环二苯并氮杂环庚三烯、丁酰苯、二苯基丁基哌啶和吲哚酮类神经安定剂。吩噻嗪的合适实例包括氯丙嗪、甲砜达嗪、硫利达嗪、醋奋乃静、氟奋乃静、奋乃静和三氟拉嗪。噻吨的合适实例包括氯普噻吨和氨砜噻吨。二苯并氮杂环庚三烯的实例是氯氮平。丁酰苯的实例是氟哌啶醇。二苯基丁基哌啶的实例是派迷清。吲哚酮的实例是莫林酮。其它神经安定剂包括克塞平、舒必利和利培酮。应当理解的是,当与主题化合物组合使用时,所述神经安定剂可以呈药学上可接受的盐的形式,例如,氯丙嗪盐酸盐、甲砜达嗪苯磺酸盐、硫利达嗪盐酸盐、醋奋乃静马来酸盐、氟奋乃静盐酸盐、醋奋乃静庚酸盐、氟奋乃静癸酸盐、三氟拉嗪盐酸盐、氨砜噻吨盐酸盐、氟哌啶醇癸酸盐、克塞平琥珀酸盐和莫林酮盐酸盐。奋乃静、氯普噻吨、氯氮平、氟哌啶醇、派迷清和利培酮通常以非盐形式来使用。
在一些实施方案中,公开的组合物可以与下列物质组合使用:减食欲剂,例如阿米雷司、胺非氯醛(amphechloral)、安非他明、苄非他明、对氯苯丁胺、氯苄雷司、氯福雷司、氯氨雷司、氯特胺、环己异丙甲胺、右芬氟拉明、右旋安非他明、安非拉酮、二苯甲哌啶乙醇、N-乙基安非他明、芬布酯、芬氟拉明、非尼雷司、芬普雷司、氟多雷司、氟氨雷司、糠甲苯丙胺、左苯丙胺、左法哌酯(levophacetoperane)、马吲哚(mazindol)、美芬雷司、甲胺苯丙酮、脱氧麻黄碱、去甲伪麻黄碱、喷托雷司、苯甲曲秦、芬美曲秦、芬特明(phentermine)、苯丙醇胺、匹西雷司和西布曲明;选择性血清素再摄取抑制剂(SSRI);卤化安非他明衍生物,包括对氯苯丁胺、氯福雷司、氯特胺、右芬氟拉明、芬氟拉明、匹西雷司和西布曲明;和其药学上可接受的盐。
在一些实施方案中,公开的组合物可以与抗抑郁剂或抗焦虑剂组合使用,包括:去甲肾上腺素再摄取抑制剂(包括叔胺三环和仲胺三环)、选择性血清素再摄取抑制剂(SSRI)、单胺氧化酶抑制剂(MAOI)、单胺氧化酶的可逆性抑制剂(RIMA)、血清素和去甲肾上腺素再摄取抑制剂(SNRI)、促皮质素释放因子(CRF)拮抗剂、α-肾上腺素受体拮抗剂、神经激肽-1受体拮抗剂、非典型性抗抑郁剂、苯并二氮卓类、激动剂或拮抗剂(特别是5-HT.sub.lA部分激动剂)以及促皮质素释放因子(CRF)拮抗剂。具体的药剂包括:阿米替林、氯米帕明、多塞平、丙咪嗪和曲米帕明;阿莫沙平、地昔帕明、马普替林、去甲替林和普罗替林;氟西汀、氟伏沙明、帕罗西汀和舍曲林;异卡波肼、苯乙肼、反苯环丙胺和司来吉兰;吗氯贝胺;文拉法辛;阿瑞匹坦;安非他酮、锂、奈法唑酮、曲唑酮和维洛沙秦;阿普唑仑、利眠宁、氯硝西泮、二钾氯氮、地西泮、哈拉西泮、劳拉西泮、奥沙西泮和普拉西泮;丁螺环酮、氟辛克生、吉吡隆和伊沙匹隆、和其药学上可接受的盐。
在一些实施方案中,公开的组合物可以与下列物质组合使用:阿片剂激动剂;脂氧合酶抑制剂例如5-脂氧合酶的抑制剂;环加氧酶抑制剂,例如环加氧酶-2抑制剂;白细胞介素抑制剂,例如白细胞介素-1抑制剂;NMDA拮抗剂;一氧化氮抑制剂或一氧化氮的合成抑制剂;非甾体抗炎剂或细胞因子抑制抗炎剂,例如与诸如下列物质的化合物组合使用:醋氨酚、阿司匹林、可待因、芬太尼、布洛芬、吲哚美辛、酮咯酸、吗啡、萘普生、非那西汀、吡罗昔康、甾体止痛剂、舒芬太尼、苏林酸、替尼达普等。类似地,主题化合物可以与下列物质一起施用:止痛药;增效剂,例如咖啡因、H2-拮抗剂、二甲基硅油、氢氧化铝或氢氧化镁;解充血药,例如苯肾上腺素、苯丙醇胺、伪麻黄碱、羟甲唑啉、肾上腺素、萘唑啉、丁苄唑啉、六氢脱氧麻黄碱或左旋脱氧麻黄碱;止咳药,例如可待因、氢可酮、卡拉美芬、喷托维林或右美沙芬;利尿药;以及镇静性或非镇静性抗组胺剂。
剂型
还公开了一种药物组合物,其包含一种或多种mGluR的正构激动剂、正构拮抗剂或变构调节剂(在本文中统称为“mGluR正构或变构药物”)。所述药物组合物还可以任选地包含钙剂。或者,该钙剂可以存在于第二药物或营养组合物中。mGluR正构或变构药物和/或钙剂统称为“活性剂”。
所公开的药物组合物可以方便地以剂量单位形式来呈现,并且可以通过药学领域中熟知的任何方法来制备。所有方法包括使活性成分与组成一种或多种辅助成分的载体缔合的步骤。通常,通过使活性成分与液体载体或微细固体载体或两者均匀和紧密缔合且然后在必要时使产品成型为所需制剂来制备药物组合物。在药物组合物中,活性目标化合物以足以对疾病的过程或状态产生所需作用的量被包含。
所公开的药物组合物可以呈适于口服的形式,例如片剂、糖锭、锭剂、水性或油性混悬剂、可分散性散剂或颗粒剂、乳剂、硬或软胶囊、或糖浆或酏剂。可以根据本领域中已知的用于制造药物组合物的任何方法来制备预期用于口服的组合物,且这类组合物可以包含一种或多种选自由以下组成的组的物质:甜味剂、调味剂、着色剂和防腐剂,以便提供药学上美观和适口的制剂。片剂包含活性成分和适于制造片剂的药学上可接受的非毒性赋形剂的掺合物。这些赋形剂可以是例如:惰性稀释剂,例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;粒化剂和崩解剂,例如玉米淀粉或藻酸;粘合剂,例如淀粉、明胶或阿拉伯胶;以及润滑剂,例如硬脂酸镁、硬脂酸或滑石。片剂可以无包衣或它们可以通过已知技术而包衣,以延迟在胃肠道中的崩解和吸收并由此在较长时间内提供持续作用。例如,可以采用时间延迟材料例如单硬脂酸甘油酯或二硬脂酸甘油酯。
用于口服的制剂还可以呈硬明胶胶囊形式,其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合;或呈软明胶胶囊形式,其中活性成分与水或油介质例如花生油、液体石蜡或橄榄油混合。
水性混悬剂包含活性物质与适于制备水性混悬剂的赋形剂的掺合物。这类赋形剂是悬浮剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯基吡咯烷酮、黄蓍胶和阿拉伯胶;分散剂或润湿剂可以是天然存在的磷脂如卵磷脂、或环氧烷与脂肪酸的缩合产物例如聚氧乙烯硬脂酸酯、或环氧乙烷与长链脂肪醇的缩合产物例如十七亚乙基氧基十六醇、或环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物例如聚氧乙烯山梨糖醇单油酸酯、或环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物例如聚乙烯山梨糖醇酐单油酸酯。水性混悬剂还可以包含一种或多种防腐剂例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯、一种或多种着色剂、一种或多种调味剂和一种或多种甜味剂如蔗糖或糖精。
油性混悬剂可以通过将活性成分悬浮于植物油(例如花生油、橄榄油、芝麻油或椰子油)或矿物油(如液体石蜡)中来配制。油性混悬剂可以包含增稠剂,例如蜂蜡、硬质石蜡或十六醇。可以添加甜味剂(如上文所列出的那些甜味剂)和调味剂,以提供适口的口服制剂。这些组合物可以通过加入抗氧化剂如抗坏血酸来防腐。
适于通过加水来制备水性混悬剂的分散性散剂和颗粒剂提供活性成分与分散剂或润湿剂、悬浮剂和一种或多种防腐剂的掺合物。合适的分散剂或润湿剂以及悬浮剂是例如上文已经提到的那些。还可以存在另外的赋形剂,例如甜味剂、调味剂和着色剂。
所公开的药物组合物还可以呈水包油乳剂形式。油相可以是植物油例如橄榄油或花生油,或者矿物油例如液体石蜡,或这些的混合物。合适的乳化剂可以是天然存在的树胶,例如阿拉伯胶或黄芪胶;天然存在的磷脂,例如大豆卵磷脂;和衍生自脂肪酸和己糖醇酐的酯或偏酯,例如山梨糖醇酐单油酸酯;以及所述偏酯与环氧乙烷的缩合产物,例如聚氧乙烯山梨糖醇酐单油酸酯。乳剂还可以包含甜味剂和调味剂。糖浆和酏剂可以用甜味剂例如甘油、丙二醇、山梨糖醇或蔗糖来配制。这类制剂还可以包含缓和剂、防腐剂、调味剂和着色剂。
公开的药物组合物可以呈无菌可注射水溶液、胶束制剂或油性混悬剂形式。混悬剂可以根据已知工艺使用已在上文提及的那些合适的分散剂或润湿剂以及悬浮剂来配制。无菌可注射制剂还可以是在肠胃外可接受的非毒性稀释剂或溶剂中的无菌可注射溶液或混悬剂,例如在1,3-丁二醇中的溶液。可以采用的可接受媒介物和溶剂是水、林格氏溶液(Ringer's solution)和等渗氯化钠溶液。另外,传统上采用无菌不挥发性油作为溶剂或悬浮介质。为此,可以使用任何温和的不挥发性油包括合成的单甘油酯或二甘油酯。另外,脂肪酸例如油酸被用于制备可注射剂。
mGluR正构或变构药物以治疗有效量存在于药物组合物中。例如,适当的剂量水平可以为约0.01至500mg/kg患者体重/天,其可以以单剂量或多剂量形式来施用。在一些实施方案中,剂量水平为约0.1至约250mg/kg/天;更优选为约0.5至约100mg/kg/天。合适的剂量水平可以为约0.01至250mg/kg/天、约0.05至100mg/kg/天或约0.1至50mg/kg/天。在此范围内,剂量可以为0.05至0.5、0.5至5或5至50mg/kg/天。对于口服施用,所述组合物优选以片剂、胶囊剂、囊片或丸剂形式来提供,其包含1.0至1000毫克活性成分,具体而言1.0、5.0、10、15、20、25、50、75、100、150、200、250、300、400、500、600、750、800、900和1000毫克活性成分,从而根据被治疗的病人的症状调整剂量。所述化合物可以以每天1至4次的方案来施用。具有本领域内的知识和技术的医疗保健提供者可以调整这种给药方案,以提供最佳的治疗反应。然而,应该理解的是,用于任何特定患者的具体剂量水平和给药频率可以是变化的并且将取决于多种因素,包括:所使用的具体化合物的活性、化合物的代谢稳定性和作用时间长度、年龄、体重、总体健康状况、性别、饮食、施用的方式和次数、排泄速率、药物组合、具体病状的严重性以及经受治疗的主体。
治疗性施用
本文公开的组合物(包括药物组合物)可以以多种方式来施用,这取决于需要局部还是全身治疗以及待治疗的区域。例如,公开的组合物可以通过口腔、肠胃外(例如,肌内、腹腔内、静脉内、ICV、脑池内注射或输注、皮下注射、积存注射或植入物)、通过吸入喷雾、鼻腔、阴道、直肠、舌下或局部施用途径来施用,并且可以单独或一起配制在含有适用于每种施用途径的药学上可接受的常用非毒性载体、佐剂和媒介物的合适剂量单位制剂中。
定义
如本文中所用,结合至特定受体亚型并且仅对该受体亚型有活性的受体拮抗剂和激动剂是“选择性”药剂,而结合至多于一个受体亚型并对其有活性的那些是“非选择性”的。“正构”配体是结合至受体的初级受体结合位点(例如与内源性神经递质(谷氨酸)结合的mGluR受体的部分)并在该位点处有活性的激动剂或拮抗剂。因此,正构剂可以与神经递质竞争地结合所述初级位点,并且可以进一步被分类为“竞争性”激动剂或拮抗剂。结合至二级受体结合位点且在一些情况下三级受体结合位点(这些位点是空间不同的结构域,内源性神经递质对其具有极少的亲和力或没有亲和力)并在这些位点处有活性的激动剂或拮抗剂被称为“变构”配体。这些变构配体是“非竞争性的”,因为即使在高浓度下,它们也不会通过竞争初级结合位点来代替内源性配体。然而,结合至受体中的变构位点的化合物可以减轻、改变、减弱、增强、减少、抑制或阻止内源性神经递质或其它正构配体与初级结合位点的结合。或者,结合至受体中的变构位点的化合物可以减轻、改变、减弱、增强、减少、抑制或阻止活化受体的生理功能,所述生理功能尤其包括离子通量调节、信号传导、磷酸化和蛋白质的募集等。激动剂或拮抗剂(无论是正构或变构的)对其在受体中的结合位点的吸引效力由该配体对结合位点的非共价吸引和排斥化学力的总和决定,并且被称为“亲和力”。高亲和力激动剂或拮抗剂将在极低浓度下结合至其在受体中的相应位点,而低亲和力分子在发生显著结合前需要更高的浓度。具有足以结合至变构位点的亲和力的激动剂或拮抗剂将使活化mGluR的生理功能产生显著变化。这类激动剂或拮抗剂在本文中被称为“变构调节剂”,并且可以展现正向(增强的生理功能)或负向(减弱的生理功能)调节。
术语“受试者”是指是施用或治疗的目标的任何个体。受试者可以是脊椎动物,例如哺乳动物。因此,受试者可以是人或兽类患者。术语“患者”是指由临床医生例如内科医生进行治疗的受试者。
术语“治疗有效的”是指所用的组合物的量是足以改善疾病或病症的一种或多种病因或症状的量。所述改善只需要减少或改变,而不一定需要消除。
术语“药学上可接受的”是指那些在合理医学判断的范围内适用于与人类和动物的组织接触而无过度的毒性、刺激性、过敏反应或与合理的效益/风险比相称的其它问题或并发症的化合物、材料、组合物和/或剂型。
术语“[Ca2+]o”是指细胞外钙的浓度,而术语“[Ca2+]i”是指细胞内钙的浓度。
术语“钙剂”是指可以调节mGluR受体附近的钙的细胞外水平的任何分子、方案、系统或方法。
已经描述了本发明的许多实施方案。然而,应该了解,可以在不脱离本发明的精神和范围的情况下作出各种修改。因此,其它实施方案在所附权利要求书的范围内。
实施例
实施例1:细胞外钙调节正构和变构配体对代谢型谷氨酸受体1α的作用
实验程序
使用Autodock-vina将L-Quis对接至ECD-mGluR1α以及铰链运动分析。为了说明L-Quis与mGluR1α的ECD的结合,使L-Quis对接至晶体结构(1EWK)中。在去除结合的内源性配体L-Glu的坐标后,将pdb文件载入Autodock工具以添加极性氢原子并选择对接中心和栅格箱。通过Autodock工具-Vina(Scripps)来实施对接工作。通过测量L-Quis的内的原子来分析结合残基。使用Dymdon分析铰链区内的L-Glu和(s)-MCPG结合位点。
使用Amber的MD模拟和相关分析。从具有PDBID 1EWK的解析度的x射线晶体结构获得针对所有模拟的初始坐标(Kunishima,N.等人(2000)Nature 407:971-977)。使用AMBER 10程序套件(Case,D.A.等人(2008)AMBER 10)在显式TIP3P水模型中实施所有的模拟(Jorgensen,W.L.等人(1983)J.Chem.Phys.79:926-935),其使用全原子Cornell等人(Cornell,W.D.等人(1995)J.Am.Chem.Soc.117:5179-5197)力场的修改版本和肽ω键的重新优化的双面角参数(Urmi,D.等人(2009)J.Phys.Chem.113:16590-16595)。晶体结构仅含有PHE底物。将Ca2+离子放置在由残基D318、D322和E325限定的建议的Ca2+结合位点。在平衡期间使用NOE约束进行最初的2ns模拟以重新定向Ca2+结合位点中的侧链残基,但在实际模拟期间不使用约束。对野生型mGluR和三种突变mGluR实施总共四种MD模拟,每种为50ns。突变为D318I、D322I和E325I。首先,使结构最小化以在每种复合物中实现能量最低的构象。然后使所述结构平衡2ns,从平衡结构开始MD模拟。在模拟期间,使用0.002ps的积分时间步长来求解牛顿运动方程。使用Particle Mesh Ewald方法计算长程静电相互作用(Darden,T.等人(1993)J.Chem.Phys.98:10089-10092),并将的截止值应用于非键相互作用。使用SHAKE算法约束涉及氢原子的所有键(Ryckaert,J.P.等人(1977)J.Comput.Phys.23:327-341)。所述模拟是在300K的温度和1bar的压力下进行。使用Langevin恒温器以1.0ps-1的碰撞频率来调节温度。每隔500步(1ps)保存轨迹线一次。然后使用Amber 10中的ptraj模块分析轨迹线。
mGluR1α变体的构建体、定点诱变和表达。通过柔性接头GGNSGG(SEQ ID NO:1)将红色荧光蛋白mCherry用基因方法标记至mGluR1α的C端(Jiang,Y.等人(2010)J Biol Chem285:33463-33474)。使用定点诱变试剂盒(Strategene)引入点突变。将HEK293细胞接种和培养在玻璃盖玻片上。利用lipofectamine2000(Invitrogen)将mGluR1α和其突变体转染至细胞中。然后另外孵育细胞两天,以便mGluR1α和其突变体以足够水平表达以供研究使用。用4%甲醛将细胞固定在盖玻片上,并用DAPI使细胞核染色。通过使用共焦显微术在587nm下测量红色荧光来检测mGluR1α和其变体的表达。
测定[Ca2+]o对L-Quis激活mGluR1α和其突变体的影响。如所描述进行[Ca2+]i的测量(Huang,Y.等人(2007)J Biol Chem 282:19000-19010)。简言之,将野生型mGluR1α瞬时转染至细胞内并另外培养两天。随后使用含在2mL生理盐水缓冲液(10mM HEPES、140mMNaCl、5mM KC1、0.55mM MgCl2、1mM CaCl2,pH 7.4)中的4μM Fura-2AM加载盖玻片上的细胞30min。然后在室温下将盖玻片固定在荧光显微镜的载物台上的浴室中。使用Leica DM6000荧光显微镜随着在存在或不存在[Ca2+]o的情况下渐进性增加L-Quis的浓度实时收集来自在340或380nm下激发的单细胞的510nm下的Fura-2发射信号。进一步分析由340或380nm激发所产生的在510nm下发射的荧光的比率,以获得作为L-Quis变化的函数的[Ca2+]i反应。只选择表达mCherry的单个细胞供分析使用。
测量在0.5mM s-MCPG的存在下mGluR1α对[Ca2+]o或L-Glu的[Ca2+]i反应。用于测量[Ca2+]i反应的方法如上所述。在(s)-MCPG的存在下,于Fura-2加载后,将细胞与含在盐水缓冲液中的0.5mM(s)-MCPG孵育大于30分钟。然后,通过在1.8mM[Ca2+]o的存在下增加L-Glu的浓度或通过在含或不含0.5mM(s)-MCPG的盐水缓冲液中逐步增加[Ca2+]o来测量mGluR1α对[Ca2+]o或L-Glu的敏感性。记录在首次观察到mGluR1α的[Ca2+]i反应时的L-Glu浓度,然后使其饱和。
测定[Ca2+]o对Ro 67-4853对mGluR1α的效力的影响。如上所述使用Fura-2AM实时监测[Ca2+]i。Ro 67-4853在没有L-Glu的情况下不增强mGluR1α(Hepler,R.W.等人(2006)Biochemistry 45:15157-15167;Nemeth,E.F.等人(1998)Proc Natl Acad Sci USA.95:4040-4045)。为了获得[Ca2+]i读数,将表达mGluR1α的HEK293细胞与0.5mM Ca2+和5nM Ro67-4853预孵育至少10分钟。将载有Fura-2AM的细胞固定到充满盐水缓冲液的隔室中。通过在0.5mM或1.8mM[Ca2+]o的存在下逐步增加Ro 67-4853的浓度,如前所述通过响应于[Ca2+]i变化的fura-2AM的比率变化记录[Ca2+]i。通过比较在灌注缓冲液中的两种不同的Ca2+浓度下由Ro 67-4853引起的细胞内Ca2+反应来分析[Ca2+]o的影响。为了测定Ro 67-4853对mGluR1α的[Ca2+]o敏感性的影响,当[Ca2+]o增加时,使用额外的30nM或300nM Ro 67-4853。
测量mGluR1α在CPCCOEt的存在下对[Ca2+]o或L-Glu的[Ca2+]i反应。在盖玻片被固定在显微镜中后,用含有0、5或40μM CPCCOEt的盐水缓冲液灌注细胞10min以上。将渐增浓度的[Ca2+]o或L-Glu添加到存在不同浓度的CPCCOEt的隔室中,并记录[Ca2+]i反应。
测定[Ca2+]o对[3H]-L-Quis结合至mGluR1α和其突变体的影响。如前所述,将被野生型mGluR1α或其突变体瞬时转染的HEK293细胞维持在5%CO237℃培养器中另外48小时。然后将细胞收集在冰冷的低渗缓冲液(20mM HEPES、100mM NaCl、5mM MgCl2、5mM KC1、0.5mM EDTA和1%蛋白酶抑制剂,pH 7.0-7.5)中。使用低渗缓冲液冲洗细胞沉淀两次,以去除细胞碎片中的L-Glu。将粗制膜蛋白(100μg)与30nM[3H]-L-Quis在100μL低渗缓冲液中混合。通过测量在200μM L-Glu的存在下的结合的[3H]-L-Quis来测定非特异性结合。为了研究[Ca2+]o对L-Quis结合至mGluR1α的影响,使用浓度渐增的[Ca2+]o。将反应混合物在冰上孵育至少1小时,并使用Brandel细胞收集器在真空下将膜结合[3H]-L-Quis捕获滤纸上。然后将滤纸转移到闪烁液中,并使用Beckman LS 6500多用闪烁计数器检测[3H]-L-Quis。
结果
预测的[Ca2+]o结合位点与正构激动剂和拮抗剂结合位点相邻。利用最近开发的计算算法,在mGluR1α的ECD的铰链区内鉴定出Ca2+结合位点(Jiang,Y.等人(2010)J BiolChem 285:33463-33474)。图1显示预测的Ca2+结合位点由D318、E325、D322和天然激动剂L-Glu的羧酸侧链组成,在mGluR1α的ECD的铰链区中,与报道的L-Glu结合位点相邻。D318参与L-Glu结合和Ca2+结合二者(Jiang,Y.等人(2010)J Biol Chem 285:33463-33474)。
使用受体的ECD的晶体结构(1EWK,闭-开形式)和Autodock-Vina程序,建立正构激动剂L-Quis的结合位点的模型。如图1B中所示,激动剂L-Quis的对接结合位点与先前由晶体结构表明的L-Glu结合残基十分一致。预测的Ca2+结合位点还与L-Quis口袋相邻并且与L-Quis的相互作用类似于L-Glu(图1B)。在与正构拮抗剂(s)-MCPG复合的mGluR1的报道晶体结构(PDBID:1ISS)中,(s)-MCPG与叶片1(lobe 1)(LB1)中的Y74、W110、S165、T188和K409以及叶片2(LB2)中的D208、Y236和D318相互作用(图1B)(Tsuchiya,D.等人(2002)Proc NatlAcad Sci USA.99:2660-2665)。它与L-Glu共有L-Glu结合口袋的大部分残基(Tsuchiya,D.等人(2002)Proc Natl Acad Sci USA.99:2660-2665),且还与预测的Ca2+结合位点相邻。
接着进行分子动力学模拟以揭示预测的[Ca2+]o结合位点与正构配体结合位点之间的任何可能的相互作用。参与[Ca2+]o结合口袋的残基例如D318、D322和E325具有强烈的相关运动,正如鉴于它们作为[Ca2+]o结合配体的作用所预期的。另外,存在于与预测Ca2+结合位点相同的环内的残基D318和R323也同时相关。如图2中所示,大多数关键的L-Glu结合残基包括W110、S165、T188、D208、Y236、D318和R323与[Ca2+]o结合位点(D318、D322和E325)十分相关。然而,参与[Ca2+]o结合的带电残基中的突变(例如D318I和E325I)显著地减弱Ca2+结合位点与L-Glu结合口袋的相关性。突变体D318I中的Ca2+结合位点只与G293和D208相关,且突变体D325I只与Y236和G293相关。突变体D322I还展现[Ca2+]o结合位点与L-Glu结合位点之间的受损的相关性,但是程度较轻。如表2中所示,[Ca2+]o结合位点中的D318仍与L-Glu结合口袋中的四个残基相关(图2)。类似地,参与结合L-Quis和(s)-MCPG的残基也与参与预测[Ca2+]o结合位点的残基十分相关。来自这些分析和先前研究的关于[Ca2+]o结合至其位点对L-Glu介导的mGluR1活化的影响的结果表明[Ca2+]o调节正构配体对mGluR1α的作用。
基于图2中所示的相关图,观察到报道的L-Glu结合口袋与[Ca2+]o结合位点(D318、D322和E325)的相关性。该表格中列出了具有大于0.3的绝对相关值的残基。应该注意的是,WT在L-Glu结合位点中具有五个与[Ca2+]o结合位点1相关的残基(加阴影的部分不包括,因为它们存在于与[Ca2+]o结合位点相同的环中并且将具有相同的运动),而在变体D318I和E325I中仅在两个残基之间具有相关性,且在D322I中为四个残基。加粗的残基位于与[Ca2 +]o结合位点相同的环中,且它们默认具有与[Ca2+]o结合位点相同的运动。
Ca2+通过经由与受体的[Ca2+]o结合位点1相互作用增加[3H]-L-Quis结合来增强L-Quis使mGluR1α活化的敏感性。为了测试[Ca2+]o对正构激动剂L-Quis使mGluR1α活化的影响,使用被mGluR1α瞬时转染且负载有fura-2的HEK293细胞,通过测量[Ca2+]i的变化进行单细胞荧光成像分析。为了消除从细胞分泌的微量L-Glu的潜在影响,使用细胞的连续灌流进行实验。图3A-D表明,L-Quis以类似于L-Glu使受体活化的方式诱导由mGluR1介导的细胞内钙反应。[Ca2+]o表现为L-Quis反应的PAM且诱导关于mGluR1α活化的L-Quis CRC(浓度-反应曲线)的左移(图3A-D)。在没有[Ca2+]o的情况下(具有少于2μM钙的Ca2+游离缓冲液),关于L-Quis使mGluR1α活化的EC50为12.8nM。添加1.8mM[Ca2+]o将L-Quis的EC50减少至2.8nM(约4.6倍)(图3D,表3)。这种[Ca2+]o介导的L-Quis的效力增加类似于[Ca2+]o对mGluR1被其天然激动剂L-Glu活化的作用(Jiang,Y.等人(2010)J Biol Chem285:33463-33474)。
为了测试这种[Ca2+]o介导的L-Quis的效力增加是否经由受体的ECD中的预测的[Ca2+]o结合位点而发生,检查在与铰链区中的正构结合位点相邻的[Ca2+]o结合位点周围具有突变的三种mGluR1变体。E325的带负电荷的侧链对mGluR1结合[Ca2+]o是重要的,且不直接参与L-Glu结合(Jiang,Y.等人(2010)J Biol Chem 285:33463-33474)。去除mGuR1变体E325I中的[Ca2+]o结合配体残基降低了效力,在没有[Ca2+]o的情况下使EC50从12.6nM增加至20nM(图3D和表3)。重要的是,这种突变在1.8mM[Ca2+]o中由[Ca2+]o介导的L-Quis的效力增强从4.6倍显著减少至1.6倍,尽管E325I突变体的L-Quis介导的活化的效力和功效相对于WT mGluR1仍然是增强的(图3A-D)。另一方面,突变体D322I对L-Quis的反应在不存在和存在[Ca2+]o的情况下均展现WT样行为(图3A-D,表3),这与D322促进[Ca2+]o结合的程度较低一致(只有其主链氧充当配体原子)。还观察到了Ca2+对D332I的L-Glu反应的WT样调节(Jiang,Y.等人(2010)J Biol Chem 285:33463-33474)。这些[Ca2+]i成像数据表明:[Ca2+]o在调节L-Quis使mGluR1α活化方面起关键作用,这可能是经由[Ca2+]o在预测的[Ca2+]o结合位点处的相互作用。
在不存在或存在[Ca2+]o的情况下,使用用放射性L-Quis([3H]-L-Quis)的直接结合分析来评估[Ca2+]o对[3H]-L-Quis结合至mGluR1α或其变体(在预测的[Ca2+]o结合配体残基处具有突变)的影响。L-Quis以在30nM范围内的KD结合至表达于HEK293中的野生型受体。L-Glu通过竞争类似的正构结合口袋减少L-Quis结合(图1B、图4B插图)。[Ca2+]o显著增强L-Quis与野生型受体的结合,其中EC50在0.3mM的范围内(图3E,表3)。去除关键[Ca2+]o结合残基E325上的负电荷的变体E325I消除了L-Quis结合,且这种效应不受添加L-Glu或[Ca2+]o的影响(Kd>20mM)(表3)。在另一方面,变体D322I保留了野生型受体对L-Quis的结合性质,表明其在L-Quis结合中的必要作用较低(图3E),这与早先描述的其在激活[Ca2+]i增加中的作用一致。综上所述,对[Ca2+]i反应和L-Quis结合二者的研究表明:[Ca2+]o通过经由与铰链区中的预测[Ca2+]o结合位点1的相互作用直接调节L-Quis与mGluR1的结合来增强L-Quis对mGluR1的活化作用。
(s)-MCPG降低mGluR1α对L-Glu和[Ca2+]o的敏感性。使用L-Glu作为正构激动剂评估[Ca2+]o对通过不同机制作用于mGluR1的各种mGluR1配体的影响,因为L-Glu是该受体的体内生理活化剂。如图4中所示,(s)-MCPG诱导L-Glu诱发的[Ca2+]i反应的浓度依赖性下降(图4A)。浓度为0.5mM的(s)-MCPG引起L-Glu CRC的平行右移,并使L-Glu的EC50从1.7μM增加至3.7μM。这与MCPG在正构L-Glu结合位点处作为竞争性拮抗剂的已知作用相一致。
有趣的是,图4A显示:即使在不添加L-Glu的情况下,MCPG也诱导5mM[Ca2+]o诱导的[Ca2+]i反应的浓度依赖性抑制。与MCPG对针对L-Glu的反应的影响不同,MCPG不完全阻断对[Ca2+]o的反应。这与以下假设一致:MCPG通过在与变构调节对[Ca2+]o的反应的位点不同的位点处起作用而抑制对[Ca2+]o的反应。MCPG还诱导[Ca2+]o CRC的右移。[Ca2+]o的EC50增加约1.7倍(分别从0mM MCPG下的3.5mM增加至0.5mM MCPG下的6.0mM)(图4C,表4)。对[Ca2+]o的最大反应不受0.5mM MCPG的影响。然而,如上所述,更高浓度的MCPG不完全阻断5mM[Ca2+]o的最大效应。
NAM CPCCOEt非竞争性抑制L-Glu诱导的和[Ca2+]o诱导的mGluR1α活化。已知CPCCOEt是mGluR1的选择性非竞争性负向变构调节剂(NAM),其结合至该受体的第七TMD中的残基T815和A818(Harrington,P.E.等人(2007)Current medicinal chemistry 14:3027-3034)(图1)。如图5A中所示,L-Glu引发的[Ca2+]i反应在5和40μM CPCCOEt的存在下显著下降。在40μM CPCCOEt的存在下,最大反应降低至对照水平的仅约一半,而EC50值从1.7μM增加至10.1μM(图5A,表5)。为了测定CPCCOEt对[Ca2+]o使mGluR1α活化的影响,检查CPCCOEt对[Ca2+]o诱导的[Ca2+]i反应的影响。图5B显示:CPCCOEt显著抑制mGluR1α的[Ca2+]o敏感性。在5μM CPCCOEt的存在下,mGluR1α针对[Ca2+]o的EC50从3.5mM增加至14.7mM。浓度为40μM的CPCCOEt产生甚至更高的28.7mM的EC50值(图5B,表5)。40μM CPCCOEt还显著降低最大反应,但5μM CPCCOEt下的最大反应仍然是相当的。这表明30mM[Ca2+]o无法完全逆转由CPCCOEt引起的拮抗作用,且因此CPCCOEt对mGluR1α的[Ca2+]o反应的抑制作用似乎是非竞争性的(图5B,表5)。
mGluR1αPAM Ro 67-4853增强[Ca2+]o对mGluR1的活化作用。CPCCOEt抑制[Ca2+]o对mGluR1的活化作用的发现表明:mGluR1的跨膜结构域中的CPCCOEt位点和受体的ECD中的[Ca2+]o结合位点以类似于正构L-Glu结合位点与变构CPCCOEt位点之间的相互作用的方式相互作用。进行类似的实验以确定结合至mGluR1α的TMD的胞外环的mGluR1 PAM Ro67-4853(Lavreysen,H.等人(2003)Molecular pharmacology 63:1082-1093;Litschig,S.等人(1999)Molecular pharmacology 55:453-461)(图1B)是否也可以增强对[Ca2+]o的反应。图6A显示:通过添加10或100nM Ro 67-4853增强了L-Glu诱导的WT mGluR1α的活化(使用单细胞[Ca2+]i成像)。然后检查在没有L-Glu的情况下,Ro 67-4853对野生型mGluR1α的[Ca2+]o敏感性。图6B显示30nM和300nM Ro 67-4853均增强由[Ca2+]o诱导的[Ca2+]i反应,将对于[Ca2 +]o的EC50值从3.5mM分别减少至2.1mM和0.7mM。与Ro 67-4853对L-Glu反应的影响一样,Ro67-4853没有改变对[Ca2+]o的最大反应(图6B和表6)。
为了进一步评价Ro 67-4853对mGluR1α的影响,将瞬时表达mGluR1α的HEK293细胞与0.5mM Ca2+和5nM Ro 67-4853预孵育最多10分钟,且然后测试对多种浓度的Ro 67-4853的反应。在0.5mM[Ca2+]o的存在下,Ro67-4853以浓度依赖性方式增强L-Glu诱导的mGluR1α活性。将[Ca2+]o增加至1.8mM提高Ro 67-4853对mGluR1α的效力(图6C)。与此同时,EC50值从20.7nM降低至10.0nM(图6C,表6)。有趣的是,当用Ro 67-4853处理细胞时,观察到[Ca2+]i振荡。类似于Ca2+敏感受体,观察到三种不同模式的反应(Huang,Y.等人(2010)J Biol Chem285:35919-35931)。大多数细胞展现[Ca2+]i的瞬时峰值。一些细胞在第一峰值后开始振荡,而其它细胞具有瞬时峰,且振荡在几分钟后首次出现。通过分析振荡细胞的数量占应答细胞的总数的比例,相比于0.5mM[Ca2+]o中的细胞,1.8mM[Ca2+]o显著增加振荡细胞的数量。振荡的起始点也向左位移。这表明[Ca2+]o增强Ro 67-4853在激活mGluR1α方面的效力。
为了理解[Ca2+]o对这种变构调节剂的作用(经由TMD起作用)的调节的确是[Ca2+]o结合至ECD中的预测[Ca2+]o结合位点1的结果(例如,图1),使用关键[Ca2+]o结合配体残基突变的mGluR变体E325I来进行研究。图1B显示:E325不直接参与L-Glu结合,且变体E325I能够以类似于WT的方式感受L-Glu和激活mGluR1α(Jiang,Y.等人(2010)J Biol Chem285:33463-33474)。图7A显示添加30μM L-Glu增强E325I对Ro 67-4853的反应性。值得注意的是,图7B显示:在没有L-Glu的情况下,E325I在无[Ca2+]o盐水中对10μM Ro 67-4853有反应。使[Ca2+]o从0增加至5.0mM不影响E325I对Ro 67-4853的敏感性,但提高[Ca2+]o增加WTmGluR1α对300nM Ro 67-4853的反应(图7B)。这表明使Ca2+结合位点突变(E325I)消除了Ca2 +对Ro 67-4853的作用,但WT mGluR1α不是如此。为了确定Ro67-4853是否使受体饱和,将更高浓度的PAM应用于WT mGluR1和E325I。如图7B中所示,更高浓度的Ro 67-4853增加WTmGluR1和E325I二者的反应。这种结果表明,[Ca2+]o在其位于铰链区中的预测位点处的结合对于这种调节剂的正向变构作用是必要的。
讨论
如本文中所公开,[Ca2+]针对各种正构和变构配体对mGuRla的作用具有显著的调节作用,如使用被受体转染的HEK293细胞中的功能性读数(即,[Ca2+]i反应)所评估。[Ca2+]o对本文所研究的化合物(包括正构激动剂L-Quis、正构拮抗剂MCPG以及变构调节剂例如PAMRo 67-4853和NAM CPCCOEt)具有几种不同的影响。
如图1中所示,预测的[Ca2+]o结合位点与激动剂L-Quis和拮抗剂MCPG的预测的正构结合位点部分重叠。[Ca2+]o影响[L-Glu]o诱导的受体活化。与此一致的是,[Ca2+]o以类似方式增强L-Quis对mGluR1α的活化作用。通过结合至ECD-mGluR1上的Ca2+结合位点,[Ca2+]o能够诱导PIP2的水解,从而增加IP3和Ca2+从ER释放(Jiang,Y.等人(2010)J Biol Chem285:33463-33474)。[Ca2+]o被证明与L-Glu协同地激活mGluR1α(Jiang,Y.等人(2010)J BiolChem 285:33463-33474)。然而,GPCR的活化还诱导Ca2+内流通过由钙库操纵的Ca2+进入通道。通过利用Gd3+(这些Ca2+通道的抑制剂),注意到mGluR1α仍能够诱导[Ca2+]i增加。但将这与Ca2+诱导的反应曲线相比,Gd3+反应使该曲线回到基线。这表明从ER释放的Ca2+主要诱导瞬时峰,而Ca2+内流提高反应的平台期部分。渐增的[Ca2+]o增强L-Quis结合至过度表达mGluR1α的HEK293细胞,而突变体E325I消除[Ca2+]o对mGluR1的这种活化作用(图3)。此外,在极低的[Ca2+]o的存在下观察到L-Quis结合与L-Glu结合的明显差异。使用mGluR1α的纯化ECD,Jingami等人报道[Ca2+]o增强由L-Quis和L-Glu诱导的Trp荧光的增加(Suzuki,Y.等人(2004)J Biol Chem 279:35526-35534),但报道称[Ca2+]o对L-Quis结合没有影响(Selkirk,J.V.等人(2001)Neuropharmacology 40:645-656)。Nash等人还观察到,[Ca2+]o在由mGluR1α介导的CHO细胞中产生更高的平台期[Ca2+]i反应和更多的IP3累积(Nash,M.S.等人(2001)J Biol Chem 276:19286-19293),但是不影响[Ca2+]i的瞬时增加。因此,所公开的[Ca2+]o增强L-Quis诱导的[Ca2+]i反应和L-Quis与受体的结合的观察结果具有类似于[Ca2+]o调节L-Glu对mGluR1α的作用的生理含义。图1显示:在x射线结构(PDBID:1ISS)中,预测的[Ca2+]o结合位点的位置与mGluR1中的(s)-MCPG结合口袋相邻,所述结合口袋位于ECD的铰链区中且占据参与L-Glu结合的大部分残基(Tsuchiya,D.等人(2002)Proc Natl AcadSci USA.99:2660-2665)。测试浓度逐渐增加的正构拮抗剂(s)-MCPG对[Ca2+]o诱导的mGluR1α信号传导的影响。如图4中所示,(s)-MCPG降低mGluR1α的[Ca2+]o敏感性(图4A和4C)。增加[Ca2+]o或L-Glu的浓度克服由(s)-MCPG诱导的抑制作用(图4)。令人感兴趣地注意到,(s)-MCPG无法完全阻断mGluR1的[Ca2+]o敏感性(图4C)。发现由mGluR1α介导的[Ca2+]o诱导的反应仅受(s)-MCPG部分拮抗(Kubo,Y.等人(1998)Science 279:1722-1725)。(s)-MCPG被证明能够在瞬时表达mGluR1的非洲爪蟾(Xenopus laevis)卵母细胞中完全抑制由L-Glu增强的Ca2+活化Cl-电流(Kubo,Y.等人(1998)Science 279:1722-1725)。这些数据表明[Ca2 +]o调节正构配体对mGluR的作用。
所观察到的[Ca2+]o调节的正构效应可能取决于预测的[Ca2+]o结合位点与针对正构激动剂和拮抗剂的相邻结合位点的通信。使用AutoDock-Vina在此预测的L-Quis结合口袋与报道晶体结构中的L-Glu结合口袋大量重叠(表7)。D318的侧链参与[Ca2+]o结合和激动剂结合。突变D318I消除对[Ca2+]o的敏感性和对L-Glu的反应性(Jiang,Y.等人(2010)JBiol Chem 285:33463-33474)。在此研究中,它还完全消除L-Quis介导的mGluR1活化(图3E)。一致的是,突变体T188A、D208A、Y236A和D318A消除了受体对L-Quis和L-Glu的敏感性,而突变体R78E和R78L展现明显受损的L-Quis结合(Levant,J.A.等人(1973)The NewEngland journal of medicine 289:555-558;Sato,T.等人(2003)The Journal ofbiological chemistry 278:4314-4321)。关键残基E325参与[Ca2+]o结合,且突变体E325I确实显著损害受体对[Ca2+]o和L-Glu的敏感性(图3)。另一方面,变体D322I使[Ca2+]o对L-Quis和L-Glu激动剂作用的调节作用减少地较少,并且与其在[Ca2+]o结合中仅贡献主链配体原子的较小作用一致(图1)。
所观察到的[Ca2+]o对mGluR1的正构激动剂和拮抗剂的反应的影响与本文对mGluR的ECD中的铰链区的相关运动进行的分子动力学研究一致(图2,表2)。观察到在预测的[Ca2 +]o结合位点中的残基与L-Glu、L-Quis和MGPG所共有的参与正构结合位点的残基之间存在密切的相关性。有趣的是,[Ca2+]o结合位点的突变在很大程度上消除了这种相关性。图1A显示:铰链区中的预测的[Ca2+]o结合位点在I组mGluR例如mGluR1和mGluR5(Jiang,Y.等人(2010)J Biol Chem 285:33463-33474)、钙敏感受体和[Ca2+]o的味觉受体T1R3(Dorr,P.等人(2005)Antimicrobial agents and chemotherapy49:4721-4732)中是保守的。在我们先前的研究中,[Ca2+]o表现出与L-Glu激活mGluR1α的协同作用(Jiang,Y.等人(2010)J BiolChem 285:33463-33474)。[Ca2+]o调节作用于mGluR的正构配体的作用是经由在ECD的铰链区处的通信。L-Phe和其它氨基酸结合至CaSR的铰链区中的位点可能与铰链区中的预测[Ca2+]o结合位点通信,以增加受体对[Ca2+]o的敏感性(Huang,Y.等人(2009)Biochemistry48:388-398;Huang,Y.等人(2007)J Biol Chem282:19000-19010;Conigrave,A.D.等人(2007)The Journal of nutrition137:1524S-1527S;discussion 1548S;Zhang,Z.等人(2002)J Biol Chem277:33727-33735)。近年来,已经发现C家族GPCR的越来越多的成员展现变构调节剂对主要正构激动剂的协同调节。已知结合至人类味觉受体的铰链区的甜味增强剂稳定受体的活性形式,从而导致改变的甜味感知,而IMP和L-Glu也协同地激活鲜味受体(Zhang,F.等人(2010)Proc Natl Acad Sci USA.107:4752-4757;Zhang,F.等人(2008)Proc Natl Acad Sci USA.105:20930-20934)。还令人感兴趣地注意到,在mGluR的ECD结构域处起作用的建议的变构配体位于铰链区(Acher,F.C.等人(2011)Neuropharmacology60:102-107;Ogawa,H.等人(2010)Protein science:a publication of the ProteinSociety 19:544-557)。因此,公开的证据强烈地暗示ECD的铰链区在调节小分子配体对C家族GPCR的作用方面的作用。
关于靶向TMD的变构调节剂,mGluR1α的正向和负向调节剂的结合位点是不同的(Hemstapat,K.等人(2006)Molecular pharmacology 70:616-626)。这些变构调节剂有效地调节L-Glu对受体的活化,但关于内源性矿物离子Ca2+对这些调节剂的影响的了解很少。在此研究中,进一步评估[Ca2+]o对CPCCOEt(NAM)和Ro 67-4853(PAM)的影响。
已知非竞争性NAM CPCCOEt通过结合至第七TMD上的T815和A818抑制L-Glu反应(Rodriguez,A.L.等人(2005)Molecular pharmacology68:1793-1802;Brauner-Osbome,H.等人(1999)Neuroreport 10:3923-3925)。图5中所示的数据支持以下观点:充当非竞争性抑制剂的CPCCOEt也可以减少mGluR1α的[Ca2+]i反应。有趣的是,渐增的[Ca2+]o恢复受体的[Ca2+]o敏感性。CPCCOEt不仅抑制黑素瘤细胞的增殖,而且逆转吗啡耐受性(Haas,H.S.等人(2007)The Oncol Rep 17:1399-1404;Smith,F.L.等人(2004)Eur J Pharmacol 492:137-142)。因此,该研究中的发现表明:靶向mGluR1中的[Ca2+]o结合位点的药物具有调节CPCCOEt对黑素瘤或成瘾的治疗作用的潜力。已揭示TMD中的V757对mGluR1通过PAM的活化是关键的(Nemeth,E.F.等人(1998)Proc Natl Acad Sci USA.95:4040-4045;Hemstapat,K.等人(2006)Molecular pharmacology 70:616-626)。通过分析此处观察到的[Ca2+]i瞬变和振荡,[Ca2+]o不仅降低引发[Ca2+]i振荡所需的Ro 67-4853的浓度,而且减小EC50值并增加表达mGluR1的HEK293细胞的最大反应(图6和表6)。在Ro67-4853的存在下,mGluR1α的[Ca2 +]o敏感性也被增强,这表明[Ca2+]o结合位点与Ro 67-4583的位点之间存在变构相互作用。有趣的是,Ro 67-4853仅增强生理[Ca2+]o浓度对mGluR1α的活化作用,而[Ca2+]o的进一步增加消除了Ro 67-4853的作用。这表明在生理范围内的[Ca2+]o变化可以充当类似于Ro 67-4853的PAM,且表明[Ca2+]o诱导的Ro 67-4853效力的增强可以经由TMD激活mGluR1,且TMD的活化可以增强受体对激动剂的敏感性。由于定点诱变表明Ro 67-4853连同其它PAM(Ro 01-6128和Ro 67-7476)可能共有涉及V757的相同结合口袋,因此[Ca2+]o有可能增强Ro和VU系列的其它成员的效力。
所观察到的[Ca2+]o对PAM和NAM的作用的调节可以由受体的ECD结构域与TMD的整合作用来解释。这点受到在与L-Glu结合位点相邻的预测[Ca2+]o结合位点处使用关键[Ca2 +]o结合配体残基的突变E325I的研究的支持。变体E325I显著减少[Ca2+]o对Ro 67-4853的作用的调节(图7)。结合至TMD的PAM已被证明增强L-Quis结合至mGluR1α(Nemeth,E.F.等人(1998)Proc Natl Acad Sci US A.95:4040-4045)。[Ca2+]o不完全降低MCPG的抑制作用可能是由于涉及受体的TMD区域的额外协同作用。通过将FRET对YFP/CFP标记在二聚体mGluR1α的两个胞内环2(i2)上,Muto等人观察到由L-Glu诱导的TMD重排被(s)-MCPG逆转(Tateyama,M.等人(2004)Nat Struct Mol Biol 11:637-642)。TMD与ECD区域的这种整合效应受到对缺失VFT的mGluR的研究的进一步支持。发现PAM不仅增强激动剂对全长受体的作用,而且有时可以对VFT截短受体展现强激动剂活性(El Moustaine,D.等人(2012)ProcNatl Acad Sci USA.109:16342-16347;Goudet,C.等人(2004)Proc Natl Acad SciUSA.101:378-383)。ECD的VFT不仅负责激动剂诱导的活化,而且防止PAM激活全长受体(ElMoustaine,D.等人(2012)Proc Natl Acad Sci USA.109:16342-16347;Goudet,C.等人(2004)Proc Natl Acad Sci USA.101:378-383)。综上所述,该研究揭示在铰链区中的[Ca2 +]o结合可能负责其调节其它变构调节剂的作用的能力。生理水平(1.8mM)下的[Ca2+]o增强Ro 67-4853调节mGluR1α的效力,而渐增的[Ca2+]o减少CPCCOEt的抑制作用(图5-7,表5-6)。在过去的十年里,已经针对各种受体开发出许多新型PAM和NAM,且存在开发出具有比正构激动剂可能具有的亚型特异性更高的亚型特异性的变构调节剂的可能性(Wang,L.等人(2009)J Pharmacol Exp Ther331:340-348)。由结合至受体铰链区的内源性激动剂和PAM诱导的共活化可以是C家族GPCR的共同特征。这些数据提供对mGluR1α受[Ca2+]o调节的进一步理解,且表明[Ca2+]o具有调节作用于mGluR1α的多种试剂(包括激动剂、拮抗剂和变构调节剂)的特性的潜力。
实施例2:mGluR5对[Ca2+]o的[Ca2+]i反应的测量
方法
在杜氏改良伊格尔培养基(DMEM)和10%胎牛血清(Invitrogen)上供养HEK293细胞并在具有5%CO2的加湿培养器中于37℃下培养。在转染前一天,使HEK293细胞在22x44mm盖玻片上生长,然后在lipofectamine2000(Invitrogen)的帮助下用mGluR5质粒(由Dr.Randy Hall,Emory University,Atlanta,GA馈赠)转染。使被mGluR5转染的HEK293细胞生长48小时,然后在37℃下加载含在含有10mM HEPES(pH 7.4)、140mM NaCl、5mM KC1、0.55mM MgCl2的加载缓冲液中的4μM Fura-2AM 30分钟。然后将盖玻片固定在荧光显微镜的载物台上的浴室中。使用Leica DM6000荧光显微镜随着Ca2+的渐进性增加实时记录来自在340或380nm下激发的单细胞的510nm下的Fura-2发射信号。分析由340或380nm激发所产生的在510nm下发射的荧光的比率,以获得作为[Ca2+]o变化的函数的[Ca2+]i反应。
结果
属于I组代谢型谷氨酸受体家族的mGluR5也加工位于胞外结构域中的保守Ca2+结合位点。细胞外Ca2+浓度变化诱导被mGluR5转染的细胞的细胞内Ca2+振荡。0.05mM细胞外Ca2 +浓度变化开始诱导细胞内振荡(图8)。较大的细胞外Ca2+浓度变化导致较高的振荡频率(图9和图10)。
实施例3:细胞外Ca2+对mGluR5对L-Glu、Ro-674853和L-Quis的反应的影响
方法
如上所述来培养和转染HEK293细胞。使用如前所述的方法记录细胞内Ca2+浓度。在不同的细胞外Ca2+的存在下,渐进地添加L-Glu或Ro-674853或L-Quis来激活mGluR5并监测细胞内Ca2+反应。
结果
细胞外Ca2+调节mGluR5对添加L-Glu的反应
放置在具有不同浓度的Ca2+的槽液中的细胞对添加相同量的L-Glu展现不同的反应。在没有细胞外Ca2+的情况下,能够被L-Glu活化的细胞的百分比较小,并且需要高L-Glu来增强mGluR。与0mM Ca2+槽液相比,1.8mM使得最多比例的细胞在低L-Glu(1μM)下振荡,之后是0.5mM Ca2+。另外,在没有细胞外Ca2+的情况下由高浓度L-Glu引发的细胞内Ca2+振荡展现慢很多的振荡。细胞外Ca2+可以增强L-Glu引发的mGluR5反应。
细胞外Ca2+调节mGluR5对添加Ro-674853的反应
将被mGluR5转染的HEK293细胞放置在含有0或0.5mM Ca2+的槽液中,并添加Ro-674853以刺激在细胞质膜上表达的mGluR5。在没有细胞外Ca2+的存在下,没有观察到细胞内Ca2+反应,而在实验的最后添加0.5mM Ca2+加Ro-674853可以激活mGluR5并引发细胞内Ca2+振荡,这表明mGluR5表达于所述膜上且可以被活化。在0.5mM Ca2+的存在下,在添加Ro-674853后观察到高频率Ca2+振荡,且5nM Ro-674853可以导致对mGluR5的刺激(图14A至14B)。
细胞外Ca2+调节mGluR5对添加L-Quis的反应
将被mGluR5转染的HEK293细胞放置在含有0或0.5mM Ca2+的槽液中,并添加L-Quis以刺激在细胞质膜上表达的mGluR5。在没有细胞外Ca2+供应的情况下,L-Quis几乎不能引发任何mGluR5反应,而在0.5或1.8mM Ca2+槽液中的细胞可以被添加L-Quis刺激。值得注意的是,在较高Ca2+槽液中的细胞开始在较低的L-Quis浓度下振荡。另外,当细胞存在于较高Ca2 +槽液中时,振荡频率高很多(图15和16)。进一步分析表明:当施加0.5mM或1.8mM时,更大比例的细胞显示对L-Quis刺激的反应(图17)。
实施例4:mGluR1数据汇总
方法
使被mGluR1转染的HEK293细胞在13.5x 20mm盖玻片上生长。在细胞达到90%汇合后,通过与含有125mM NaCl、5mM KCl、1.25mM CaCl2、1mM MgCl2、1mM NaH2PO4、1%葡萄糖和1%BSA的20mM HEPES(pH7.4)中的4μM Fura-2AM在37℃下孵育1h来加载这些细胞,然后用含有125mM NaCl、5mM KCl、0.5mM CaCl2、0.5mM MgCl2、1%葡萄糖和1%BSA的20mMHEPES(pH 7.4)(浴缓冲液)冲洗一次。将具有被转染的负载Fura-2的HEK293细胞的盖玻片对角地放置在含有浴缓冲液的3ml石英比色杯中。在[Ca2+]o的逐步增加期间,伴随340或380nm的交替激发测量510nm下的荧光光谱。在340或380nm下激发时于510nm下的发射光的强度的比率被用来监测[Ca2+]i的变化。将mCherry基因融合至mGluR1 pcDNA中。因此,具有550nm下的荧光强度的细胞被选择用于进一步分析。
结果
mGluR1不仅可以被谷氨酸激活,而且可以被钙激活。细胞外钙可以增强被mGluR1转染的HEK293细胞中由谷氨酸诱导的细胞内钙释放(图18和图19)。谷氨酸和细胞外钙一起将诱导细胞内钙振荡(图20和图21)。首先使用0mM钙孵育被mGluR1转染的HEK293细胞。用不同浓度的谷氨酸(1.7uM/17uM)处理这些细胞,以产生相应的瞬时峰值。在峰值返回到基线后,进一步施加0mM钙以洗掉剩余的缓冲液。然后使用3mM/6mM钙来引发mGluR1的活化,没有观察到任何反应。再用0mM钙洗掉剩余的缓冲液,且最后用谷氨酸和钙(1.7uM谷氨酸和3mM钙,17uM谷氨酸和6mM钙)处理所述细胞。产生更多的细胞反应并释放更多的细胞内钙,同时观察到钙振荡(图20和图21)。如图21中所示,由具有17uM谷氨酸和6mM钙的林格缓冲液引发的钙振荡可以持续1h。更高浓度的谷氨酸和细胞外钙使得钙振荡频率更快且峰值振幅更大。
除非另有定义,否则本文所使用的所有技术和科学术语具有如所公开发明所属的领域的技术人员通常所理解的相同含义。本文所引用的出版物以及针对其所引用的材料通过引用明确地并入。
本领域技术人员仅利用常规实验就将认识到或能够确定本文所描述的本发明的具体实施方案的许多等效方案。这些等效方案旨在涵盖于随附的权利要求书中。
Claims (26)
1.一种用于治疗受试者中的完全或部分由I组代谢型谷氨酸受体(mGluR)介导的中枢神经系统(CNS)疾病或病症的方法,其包括向所述受试者施用:
(a)一种或多种I组mGluR的正构激动剂、正构拮抗剂、正向变构调节剂或负向变构调节剂;以及
(b)调节所述正构激动剂、正构拮抗剂或变构调节剂的活性的量的用于增加或降低细胞外Ca2+水平的钙剂。
2.根据权利要求1所述的方法,其中所述I组mGluR选自由mGluR1和mGluR5组成的组。
3.根据权利要求1至2中任一项所述的方法,其中所述正构激动剂、正构拮抗剂、正向变构调节剂或负向变构调节剂选自表1中所陈述的分子。
4.根据权利要求1至3中任一项所述的方法,其中所述钙剂包括食品或钙补充剂。
5.根据权利要求1至4中任一项所述的方法,其中所述钙剂包括影响所述mGluR对钙的敏感性的神经递质或氨基酸。
6.根据权利要求1至5中任一项所述的方法,其中所述钙剂包括促进从细胞钙库的钙释放的神经递质。
7.根据权利要求1至6中任一项所述的方法,其中所述钙剂包括电或机械刺激。
8.根据权利要求1至7中任一项所述的方法,其中所述正构激动剂、正构拮抗剂、正向变构调节剂或负向变构调节剂与所述钙剂一起以单一剂量单位配制。
9.根据权利要求1至8中任一项所述的方法,其中所述疾病或病症选自由以下组成的组:抑郁症、焦虑症、药物成瘾、慢性疼痛、脆性X染色体综合症(FXS)、自闭症谱系障碍(ASD)、帕金森氏病和胃食管返流病。
10.根据权利要求9所述的方法,其包括向所述受试者施用所述一种或多种I组mGluR的正构拮抗剂或负向变构调节剂。
11.根据权利要求10所述的方法,其中所述正构拮抗剂包括(s)-MCPG。
12.根据权利要求10所述的方法,其中所述负向变构调节剂包括CPCCOEt。
13.根据权利要求1至8中任一项所述的方法,其中所述疾病或病症选自由以下组成的组:精神分裂症、与长期吸毒有关的认知缺陷和消退性学习中的缺陷。
14.根据权利要求11所述的方法,其包括向所述受试者施用所述一种或多种I组mGluR的正构激动剂或正向变构调节剂。
15.根据权利要求14所述的方法,其中所述正构激动剂包括L-使君子氨酸。
16.根据权利要求14所述的方法,其中所述正向变构调节剂包括Ro67-4853。
17.一种组合物,其包含一种或多种I组mGluR的正构激动剂、正构拮抗剂、正向变构调节剂或负向变构调节剂以及用于增加或降低细胞外Ca2+水平的钙剂。
18.根据权利要求17所述的组合物,其中所述I组mGluR选自由mGluR1和mGluR5组成的组。
19.根据权利要求17至18中任一项所述的组合物,其中所述正构激动剂、正构拮抗剂、正向变构调节剂或负向变构调节剂选自表1中所陈述的分子。
20.根据权利要求17至19中任一项所述的组合物,其中所述钙剂包括食品或钙补充剂。
21.根据权利要求17至20中任一项所述的组合物,其中所述钙剂包括影响所述mGluR对钙的敏感性的神经递质或氨基酸。
22.根据权利要求17至21中任一项所述的组合物,其中所述钙剂包括促进从细胞钙库的钙释放的神经递质。
23.根据权利要求17至22中任一项所述的组合物,其中所述正构激动剂包括L-使君子氨酸。
24.根据权利要求17至22中任一项所述的组合物,其中所述正构拮抗剂包括(s)-MCPG。
25.根据权利要求17至22中任一项所述的组合物,其中所述正向变构调节剂包括Ro67-4853。
26.根据权利要求17至22中任一项所述的组合物,其中所述负向变构调节剂包括CPCCOEt。
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US201361877579P | 2013-09-13 | 2013-09-13 | |
US61/877,579 | 2013-09-13 | ||
US201361909134P | 2013-11-26 | 2013-11-26 | |
US61/909,134 | 2013-11-26 | ||
PCT/US2014/055577 WO2015039003A1 (en) | 2013-09-13 | 2014-09-15 | Modulating drug effects against metabotropic glutamate receptor with extracellular calcium |
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US20030100539A1 (en) * | 2001-04-02 | 2003-05-29 | Bear Mark F. | Methods of treating neurological disorders with group I mGluR antagonists |
CN101309682A (zh) * | 2005-10-21 | 2008-11-19 | 脑细胞股份有限公司 | 通过pde抑制调节神经发生 |
EP2212284A2 (en) * | 2007-10-15 | 2010-08-04 | Amgen Inc. | Calcium receptor modulating agents |
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PL218788B1 (pl) * | 2002-03-29 | 2015-01-30 | Janssen Pharmaceutica Nv | Znakowane radioaktywnie pochodne chinoliny i jej zastosowanie |
US7085756B2 (en) * | 2003-05-08 | 2006-08-01 | International Business Machines Corporation | Methods, systems, and computer program products for web services |
AU2006245251B2 (en) * | 2005-05-12 | 2009-10-08 | Olympus Medical Systems Corp. | Biometric instrument |
US8211882B2 (en) * | 2008-03-08 | 2012-07-03 | Richard Delarey Wood | Glutamate receptor modulators and therapeutic agents |
US9333242B2 (en) * | 2012-01-19 | 2016-05-10 | Hybrid Medical, Llc | Topical therapeutic formulations |
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US20030100539A1 (en) * | 2001-04-02 | 2003-05-29 | Bear Mark F. | Methods of treating neurological disorders with group I mGluR antagonists |
CN101309682A (zh) * | 2005-10-21 | 2008-11-19 | 脑细胞股份有限公司 | 通过pde抑制调节神经发生 |
EP2212284A2 (en) * | 2007-10-15 | 2010-08-04 | Amgen Inc. | Calcium receptor modulating agents |
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US20160220603A1 (en) | 2016-08-04 |
US10449216B2 (en) | 2019-10-22 |
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