Dual Allosteric Modulators of GABA-A and Nicotinic Receptors for Alzheimer's Dise

描述（由申请人提供）：海马胆碱能神经传递在学习和记忆中起着重要作用。学习和记忆障碍如阿尔茨海默病（AD）和痴呆与海马中胆碱能神经传递的减少有关。具体地，烟碱乙酰胆碱受体（nAChR）亚型a4 b2的表达在这些疾病中显著降低，而a7亚型相对保留。各种药物发现的努力都集中在创造能增加烟碱神经传递的分子上，希望这些分子能增加痴呆症患者的认知能力。除了烟碱系统之外，含有α 5亚基的GABAA受体（GABAA α 5受体）可以调节海马神经传递。选择性抑制海马体中的GABAA α 5受体功能促进了学习和记忆的动物模型中认知状态的提高，表明GABAA α 5的抑制也可能是可行的治疗策略。与α 7 nAChR一样，据报道GABAA α 5受体在轻度AD等病症中相对较少。这些观察结果表明，有助于学习和记忆的两个重要的治疗靶点存在于AD大脑中，并且可以同时靶向。我们实验室发现的一种分子是GABAA α 5受体的选择性负变构调节剂和α 7 nAChR的正变构调节剂。这种分子，称为2-228，代表了第一个已知的化合物，具有推定的认知增强特性，来源于GABAA和nACh受体的同时变构调节。所提出的研究的目标是开发α 7 nAChR的正变构调节剂，其也是GABAA α 5受体的负变构调节剂，具有比2-228更多的药物样属性。所提出的分子将显示α 7 nAChR的正调节，而不激活其他nAChR亚型（例如，a4b2、a3b4）。所提出的分子还将显示GABAA α 5受体的部分负变构调节，而对含有GABAA α 1、α 2或α 3亚基的受体没有功效。2-228及其类似物的构效关系将通过测量它们在爪蟾卵母细胞中表达的各种GABAA和nACh受体亚基上的电生理活性来推导。在啮齿动物模型中，将评价最多5种候选分子的药代动力学（PK）特征，这些候选分子满足我们的受体亚型选择性、效力和疗效选择标准，以获得超过2-228的生物利用度改善。完成拟定研究将产生一种合适的候选药物，该候选药物将成为未来研究的主题，以表征其体外和体内药理学和作用部位，最终目标是开发一种用于治疗AD和其他老年性痴呆相关认知缺陷的新药。

DESCRIPTION (provided by applicant): It is well established that hippocampal cholinergic neurotransmission plays an important role in learning and memory. Disorders of learning and memory such as Alzheimer's disease (AD) and dementia have been associated with a reduction in cholinergic neurotransmission in hippocampus. Specifically, expression of the nicotinic acetylcholine receptor (nAChR) subtype a4b2 is dramatically reduced in these disorders, while the a7 subtype is relatively preserved. A variety of drug-discovery efforts are focused on creation of molecules that will increase nicotinic neurotransmission with the hope that these molecules will increase cognition in the dementias. In addition to the nicotinic system, GABAA receptors containing the a5 subunit (GABAA a5 receptors) can modulate hippocampal neurotransmission. Selective inhibition of GABAA a5 receptor function in the hippocampus promotes an elevated state of cognition in animal models of learning and memory, suggesting that inhibition of GABAA a5 may also be a viable therapeutic strategy. Like a7 nAChRs, GABAA a5 receptors are reported to be relatively spared in conditions like mild AD. These observations suggest that two important therapeutic targets that subserve learning and memory are present in AD brains and could be targeted simultaneously. A molecule discovered in our lab is a selective negative allosteric modulator of GABAA a5 receptors AND a positive allosteric modulator of a7 nAChRs. This molecule, termed 2-228, represents the first known compound with putative cognition enhancing properties derived from simultaneous allosteric modulation of both GABAA and nACh receptors. The goal of the proposed research is to develop a positive allosteric modulator of a7 nAChRs that is also a negative allosteric modulator of GABAA a5 receptors with more drug-like attributes than 2-228. The proposed molecule will show positive modulation of a7 nAChRs without activation of other nAChR subtypes (e.g., a4b2, a3b4). The proposed molecule will also show partial negative allosteric modulation of GABAA a5 receptors with no efficacy at GABAA a1, a2, or a3 subunit containing receptors. The structure activity relationships of 2-228 and its analogs will be deduced by measuring their electrophysiological activity at various GABAA and nACh receptor subunits expressed in Xenopus oocytes. The pharmacokinetic (PK) profile of up to 5 candidate molecules that fulfill our selection criteria for receptor subtype selectivity, potency and efficacy will be evaluated for improved bioavailability over 2-228 in rodent models. Completion of the proposed studies will yield a suitable candidate(s) that will be the topic of future studies to characterize their in vitro and in vivo pharmacology and site of action, with the ultimate goal of developing a novel drug(s) for the treatment of cognitive deficits associated with AD and other senile dementias.