SELECTIVE ANXIOLYTICS VIA BZR SUBTYPE SPECIFIC LIGANDS

描述（改编自申请人摘要）： 对病理性焦虑的认识和治疗一直是一个重要课题 关注心理健康。对照组GABAA功能的改变 已知发生于焦虑症，6包括恐慌症，癫痫，7 过敏行为，7 b恐惧症，6精神分裂症，8酗酒，9盎格鲁人 综合征，7 b和瑞特综合征，10以及导致/或 复杂的药物滥用。11 1，4-苯二氮卓类药物，用于治疗焦虑症 精神障碍以及睡眠障碍表现出抗焦虑、抗惊厥、肌肉 松弛/共济失调和镇静催眠作用。5 -12 为了提高这些药物的有效性，需要选择性抗焦虑药， 不含肌松弛剂/共济失调剂和镇静催眠剂的抗惊厥药 5由于BzR（苯二氮卓受体）配体变构调节 该系统1-5 BzR亚型选择性配体的设计5，25是一种手段， 产生更好的治疗剂。5 配体亲和性、分子模拟和CoMFA分析的结合， 被用来确定BzR之间的异同 25，26这种方法允许合成的最 迄今报道的α 5 β 2 γ 2亚型选择性激动剂5a，29以及 几种有效的α 5选择性反向激动剂1a和2a（50-75倍 25，28此外，BCCt 6a（中性拮抗剂）31，32和3 PBC 7a具有 已显示对α 1 β 2 γ 2亚型具有选择性，前者 叔丁基酯是迄今为止报道的体外α 1选择性最强的药剂。31，32 α 4/α 6“地西泮不敏感的”配体3a、B和4a、B再次是 迄今为止报道的最有效的选择性DI配体。这些配体作为铅 在寻找BzR亚型特异性药物的化合物。基于建模， 配体取代基的变化（手性或非手性;极性或非极性） 其占据了膜的亲脂性口袋L1、L2、L3或Ldi， 药效团/受体模型将提供所需的亚型选择性。的 先导化合物在方案I和II中示出，而目标化合物 在方案III-XI中描述。目标是开发大于150 对α 1、α 5、α 4或α 6的选择性要高出一倍（后来 α 2，α 3）亚型，以确定哪种生物学功能是 由哪种亚型介导。BzR的药理学表征 亚型水平对于理解生理过程至关重要 焦虑症的基础，包括恐慌症，6次抽搐，7次睡眠 疾病和认知，16以及设计选择性药物治疗 这些疾病状态具有降低的滥用可能性。

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.