SELECTIVE ANXIOLYTICS VIA BZR SUBTYPE SPECIFIC LIGANDS

描述(改编自申请人的摘要)： 病理性焦虑的理解和治疗长期以来一直是一个重要的课题。 对精神健康的关注。来自控件的GABAA函数的更改 已知发生在焦虑症中，6包括惊恐障碍，癫痫，7 过敏性行为，7b恐惧症，6例精神分裂症，8例酒精中毒，9例英国人 7b综合征和Rhetts综合征，10以及导致/或使药物滥用复杂化的影响。11用于治疗焦虑的1，4-苯二氮卓类药物 睡眠障碍和睡眠障碍一样，表现为抗焦虑、抗惊厥、肌肉 松弛/共济失调和镇静-催眠效果。5-12，尽管临床 这些药物的有效性需要选择性的抗焦虑药物和 不含肌松药/共济失调药和镇静催眠药的抗惊厥药 效应。5由于BZR(苯二氮卓类受体)配体通过变构调节 本系统，1-5设计BZR亚型选择性配体5，25是一种手段 产生更好的治疗剂。5 配基亲和力、分子模拟和CoMFA分析的结合 被用来确定BZR和BZR之间的异同 亚型。25，26这种方法允许合成大多数 迄今报道的α5β2γ2亚型选择性激动剂5a，29以及 几种有效的α5选择性反向激动剂1a和2a(多50-75倍 选择性)。25，28此外，BCCT 6a(中性拮抗剂)31，32和3PBC 7a 已被证明对α1β2伽马2亚型具有选择性，前者 T-丁酯是迄今为止报道的体外最具α1选择性的药物。 α4/α6“安定不敏感”配体3a，b和4a，b又是 迄今报道的最有效的选择性DI配体。这些配体起铅的作用。 化合物中寻找BZR亚型的特效剂。基于建模， 配体取代基的变化(手性或非手性；极性或非极性) 它们占据亲脂性口袋L1、L2、L3或LDI 药效团/受体模型将提供所需的亚型选择性。这个 方案一和方案二说明了先导化合物，而目标化合物 如方案三至十一所示。我们的目标是开发出150的配体。 Alpha1、Alpha5、Alpha4或Alpha6(更高版本)的选择性提高了一倍 Alpha2、Alpha3)亚型，以便确定哪种生物功能 由哪个亚型(S)介导。BZR的药理性质研究 亚型水平对于理解生理过程至关重要 焦虑的根源，包括惊恐障碍，6次抽搐，7次睡眠 障碍和认知，16以及选择治疗药物的设计 这些疾病状态减少了滥用的可能性。

DESCRIPTION(Adapted from applicant's abstract): The understanding and treatment of pathological anxiety have long been a prime concern in regard to mental health. Alterations in GABAA function from controls are known to occur in anxiety disorders,6 including panic disorder, epilepsy,7 hypersensitive behavior,7b phobias,6 schizophrenia,8 alcoholism,9 Anglemans syndrome,7b and Rhetts syndrome,10 as well as effects which lead to/or complicate drug abuse.11 The 1,4-benzodiazepines, employed to treat anxiety disorders as well as sleep disorders exhibit anxiolytic, anticonvulsant, muscle relaxant/ataxic and sedative-hypnotic effects.5-12 Despite the clinical effectiveness of these drugs there is a need for selective anxiolytics and anticonvulsants which are devoid of myorelaxant/ataxic and sedative-hypnotic effects.5 Since BzR (benzodiazepine receptor) ligands allosterically modulate this system,1-5 the design of BzR subtype selective ligands5,25 is one means to generate better therapeutic agents.5 The combination of ligand affinities, molecular modeling and CoMFA analysis has been employed to determine the similarities and differences between BzR subtypes.25,26 This approach has permitted the synthesis of the most alpha5beta2gamma2 subtype selective agonist 5a reported to date,29 as well as several potent alpha5 selective inverse agonists 1a and 2a (50-75 fold more selective).25,28 Moreover, BCCt 6a (a neutral antagonist)31,32 and 3PBC 7a have been shown to be selective for alpha1beta2gamma2 subtypes, the former t-butylester is the most alpha1 selective agent in vitro reported to date.31,32 The alpha4/alpha6 "diazepam- insensitive" ligands 3a,b and 4a,b are again the most potent selective DI ligands reported to date. These ligands serve as lead compounds in the search for BzR subtype specific agents. Based on modeling, variation of the ligand substituents (chiral or achiral; polar or nonpolar) which occupy lipophilic pockets L1, L2, L3, or Ldi of the pharmacophore/receptor model will provide the desired subtype selectivity. The lead compounds are illustrated in Schemes I and II, while the target compounds are depicted in Schemes III-XI. The goal is to develop ligands that are > 150 times more selective for either alpha1,alpha5,alpha4, or alpha6 (later alpha2,alpha3) subtypes in order to determine which biological function is mediated by which subtype(s). Characterization of the pharmacology of BzR at the subtype level is crucial for understanding the physiological processes which underlie anxiety, including panic disorder,6 convulsions,7 sleep disorders and cognition,16 as well as the design of selective agents to treat these disease states with reduced abuse potential.