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

描述(申请人提供)：众所周知，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)和痴呆症，与海马区胆碱能神经传递减少有关。具体地说，在这些疾病中，烟碱型乙酰胆碱受体(NAChR)亚型a4b2的表达显著减少，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尼古丁神经传递的分子上，希望这些分子能提高痴呆症患者的认知能力。除了尼古丁系统，含有a5亚单位的GABAA受体(GABAA a5受体)还可以调节海马神经传递。在学习和记忆的动物模型中，选择性抑制海马区的GABAA a5受体功能促进认知状态的提高，这表明抑制GABAA a5也可能是一种可行的治疗策略。与a7 nAChRs一样，GABAA a5受体据报道在轻度阿尔茨海默病等情况下相对免疫。这些观察表明，AD大脑中存在两个有助于学习和记忆的重要治疗靶点，并且可能同时成为靶点。本实验室发现的一个分子是GABAA a5受体的选择性负变构调节器和A7 nAChRs的正变构调节器。这个分子被命名为2-228，是第一个已知的化合物，它的认知增强特性来自于GABAA和NACH受体的同时变构调节。这项拟议研究的目标是开发一种A7 nAChRs的正变构调节器，它也是GABAA a5受体的负变构调节器，具有比2-228更多的药物样属性。该分子对A7nAChRs有正向调节作用，而不激活其他nAChR亚型(如a4b2、a3b4)。建议的分子还将显示GABAA a5受体的部分负变构调节，而对包含GABAA a1、a2或a3亚基的受体无效。通过测定2-228及其类似物在非洲爪哇卵母细胞中表达的不同GABAA和NACH受体亚基的电生理活性，可以推断它们的构效关系。符合我们的受体亚型选择性、效力和疗效选择标准的最多5个候选分子的药代动力学(PK)曲线将在啮齿动物模型中进行评估，以改善2-228的生物利用度。拟议研究的完成将产生一位合适的候选人(S)，这将是未来研究的主题，以确定它们的体外和体内药理和作用部位，最终目标是开发一种治疗与AD和其他老年性痴呆相关的认知障碍的新药(S)。

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.