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首要问题。已知在许多焦虑症中都会发生GABAA功能的改变，包括恐慌症、癫痫、过敏性行为、恐惧症、精神分裂症、酒精中毒、盎格鲁综合征和瑞茨综合征，以及导致/或使药物滥用复杂化的影响。用于治疗焦虑症和睡眠障碍的1，4-苯二氮卓类药物具有抗焦虑、抗惊厥、肌肉松弛/共济失调、镇静催眠和健忘作用。尽管这些药物具有临床疗效，但仍需要选择性的抗焦虑和抗惊厥药物，这些药物缺乏镇静催眠、肌肉松弛、共济失调和遗忘的作用。最近，在计算机模拟和化学合成的辅助下，我们开发了一种口服活性抗焦虑药物(1)。这种配体在BZR/GABA能系统的A1受体亚型上亲和力很差，在卵母细胞上几乎没有亲和力[Alpha1beta3Gamma2(无效)，Alpha2beta3Gamma2(完全激动剂)，Alpha3beta3Gamma2(50%激动剂)，Alpha5beta3Gamma2(10-15%激动剂)；在Alpha4/Alpha6 BZR/GABAA受体上没有亲和力]。该配体在1 mg/kg时具有口服抗焦虑活性，但在300 mg/kg时对啮齿动物没有镇静催眠、肌肉松弛或共济失调作用。它没有在歧视性刺激范例中推广到氯氮孕酮，也没有表现出任何遗忘效应。它在冲突范式的灵长类动物中也很活跃，没有肌肉放松、共济失调或镇静的迹象。这种抗焦虑剂的前药(2)在啮齿动物身上表现出类似的特征。在这项研究中，这两种抗焦虑药物是合成α2和α3亚型选择性配体的先导化合物。此外，这些药物应该是长寿的、代谢稳定的、水溶性的、临床使用的口服活性抗焦虑药物。此外，还将制备一系列新的S对映体。这些都完全符合计算机模型，而R-异构体应该是不活跃的。这些R-对映体可能是S-异构体的拮抗剂。人们认为1和2将作为先导化合物，用于构建更好的、快速起作用的、口服活性的抗焦虑药物，消除经典苯二氮类药物的镇静、共济失调、肌肉松弛和健忘副作用，并显示出减少(或不)滥用的潜力。先导化合物如图一所示，而本研究阶段的目标化合物如图2和方案1-5所示。在这项研究的第二部分(方案6和7)，重点是开发与α5β3γ2亚型结合的激动剂、拮抗剂和反向激动剂，具有400倍的亚型选择性。这些亚型选择剂的合成和药理学评估将允许将正确的生理功能分配给Alpha5亚型。这在认知/健忘和其他由海马体调节的过程中具有特别重要的意义。 已经建立了一个由12名合作者组成的网络，与我们一起在受体结合、疗效和药理学方面与我们合作，以了解/和治疗焦虑症的基本基础，以及包括年龄相关记忆缺陷在内的记忆障碍。后一项研究可能对阿尔茨海默氏症和精神分裂症也有影响。

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.