Design and Synthesis of Anxioselective Anxiolytics

描述（由申请人提供）：病理性焦虑的理解和治疗长期以来一直是心理健康方面的主要关注点。已知GABAA功能相对于对照的改变发生在许多焦虑症中，包括惊恐障碍、癫痫、过敏行为、恐怖症、精神分裂症、酒精中毒、盎格鲁人综合征和瑞特综合征，以及导致药物滥用或使药物滥用复杂化的作用。用于治疗焦虑症和睡眠障碍的1，4-苯并二氮杂卓类药物具有抗焦虑、抗惊厥、肌肉松弛/共济失调、镇静催眠和遗忘作用。尽管这些药物的临床有效性，但仍需要选择性的抗焦虑药和抗惊厥药，其不具有镇静催眠、肌肉松弛、共济失调和遗忘作用。最近，借助计算机建模和化学合成，我们开发了一种口服抗焦虑选择性抗焦虑药（1）。该配体对BzR/GABA能系统的α 1受体亚型表现出非常差的亲和力，在卵母细胞中具有近乎完美的功效特征[α 1 β 3 γ 2（无功效）、α 2 β 3 γ 2（完全激动剂）、α 3 β 3 γ 2（50%激动剂）、α 5 β 3 γ 2（10-15%激动剂）;对α 4/α 6 BzR/GABAA受体无亲和力]。该配体在1 mg/kg时具有口服抗焦虑活性，但在啮齿动物中甚至高达300 mg/kg时也没有镇静催眠、肌肉松弛或共济失调作用。它并没有推广到利血平在歧视性刺激范例，也没有表现出任何遗忘的影响。它在灵长类动物的冲突模式中也很活跃，没有肌肉松弛、共济失调或镇静的迹象。该抗焦虑剂的前药（2）在啮齿动物中表现出类似的特征。这两种抗焦虑药作为本研究中的先导化合物，用于合成α 2和α 3亚型选择性配体。此外，这些药物应该是用于临床的长效、代谢稳定、水溶性、口服活性的抗焦虑剂。此外，还将制备一系列新的S-对映体。这些完全符合计算机模型，而R-异构体应该是无活性的。希望这些R-对映体可以作为S-异构体的拮抗剂。认为1和2将作为先导化合物，用于构建更好的、快速作用的、口服活性的抗焦虑剂，其没有经典苯并二氮杂卓类的镇静、共济失调、肌肉松弛和遗忘副作用，并且表现出降低的（或没有）滥用可能性。先导化合物如图1所示，而该研究阶段的目标化合物如图2和方案1 - 5所示。在该研究的第二部分（方案6和7）中，重点是开发以>400倍亚型选择性结合α 5 β 3 γ 2亚型的激动剂、拮抗剂和反向激动剂。这些亚型选择剂的合成和药理学评价将允许将正确的生理功能分配给α 5亚型。这对于认知/遗忘症和海马体介导的其他过程特别重要。 已经建立了一个由12名合作者组成的网络，与我们一起研究受体结合，疗效和药理学，以了解/和治疗焦虑症的基本基础，以及记忆障碍，包括与年龄相关的记忆缺陷。后一项研究也可能对阿尔茨海默病和精神分裂症有影响。

DESCRIPTION (provided by applicant): 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 many anxiety disorders including panic disorder, epilepsy, hypersensitive behavior, phobias, schizophrenia, alcoholism, Anglemans syndrome and Rhetts syndrome, as well as effects which lead to/or complicate drug abuse. The 1,4-benzodiazepines, employed to treat anxiety disorders as well as sleep disorders exhibit anxiolytic, anticonvulsant, muscle relaxant/ataxic, sedative- hypnotic and amnestic effects. Despite the clinical effectiveness of these drugs, there is a need for selective anxiolytics and anticonvulsants which are devoid of the sedative-hypnotic, muscle-relaxant, ataxic and amnestic effects. Recently, with the aid of computer modeling and chemical synthesis, we have developed an orally active anxioselective anxiolytic (1). This ligand exhibits very poor affinity at the a1 receptor subtype of the BzR/GABAergic system and has a near perfect efficacy profile in oocytes [alpha1beta3gamma2 (no efficacy), alpha2beta3gamma2 (full agonist), alpha3beta3gamma2 (50% agonist), alpha5beta3gamma2 (10-15% agonist); no affinity at alpha4/alpha6 BzR/GABAA receptors]. This ligand is orally active as an anxiolytic at 1mg/kg but has no sedative-hypnotic, muscle relaxant, or ataxic effects in rodents even up to 300 mg/kg. It does not generalize to chlordiazepoxide in the discriminative stimulus paradigm, nor has it shown any amnestic effects. It is also active in primates in the conflict paradigm with no signs of muscle relaxation, or ataxia or sedation. The prodrug (2) of this anxiolytic agent exhibits a similar profile in rodents. These two anxiolytics serve as the lead compounds in this study directed toward the synthesis of alpha2 and alpha3 subtype selective ligands. Moreover, these agents should be long-lived, metabolically stable, water soluble, orally active anxiolytic agents for the clinic. In addition, a new series of S-enantiomers of these agents will be prepared. These fit the computer model perfectly, while the R-isomers should be inactive. It is hoped these R-enantiomers may be antagonists of the S-isomers. It is felt 1 and 2 will serve as the lead compounds for the construction of much better, fast acting, orally active anxiolytic agents devoid of the sedative, ataxic, muscle relaxant and amnestic side effects of classical benzodiazepines, as well as exhibit reduced (or no) abuse potential. The lead compounds are illustrated in Figure I, while the target compounds in this phase of the research are depicted in Figure 2 and Schemes 1 -5. In the second part of this research (Schemes 6 and 7) emphasis is on the development of agonists, antagonists and inverse agonists that bind to alpha5beta3gamma2 subtypes with >400 fold subtype selectivity. Synthesis and pharmacological evaluation of these subtype selective agents will permit the assignment of the correct physiological functions to alpha5 subtypes. This is of special importance here in regard to cognition/amnesia and other processes mediated by the hippocampus. A network of 12 collaborators has been established to work with us on receptor binding, efficacy and pharmacology to understand the fundamental basis of/and treat anxiety disorders, as well as memory-impairment including age associated memory deficits. This latter research may also have implications in Alzheimer's disease and schizophrenia.