Discovery of alpha4beta2 Nicotinic Receptor Antagonists as Alcohol Abuse Medications

项目总结 酒精成瘾和与过度饮酒有关的疾病在中国是一个严重的公共卫生问题 在美国和世界其他地方。目前治疗这些疾病的药物疗法 表现出有限的疗效。临床前和临床发现烟碱型乙酰胆碱受体(NAChRs)是一种 替代的，有希望的目标，为开发新的有效的药物。然而，目前还不清楚 哪些特定的nAChR亚型作为酒精奖赏效应的中介，部分是由于 组成nAChRs的不同可能的亚基组合的复杂性和缺乏效力 和选择性配体。使用组合库、脚手架排名和位置扫描策略，缓解 制药公司与Torrey Pines分子研究所合作发现了新的 已产生对42 nAChRs具有良好选择性的高亲和力nAChR拮抗剂的支架 34 nAChRs，结合亲和力和体外功能活性。当在老鼠身上进行测试时，一种铅 化合物，TPI-202以及42nAChRs的部分激动剂varenicline，但不是34nAChR定向的 配体，减弱酒精和尼古丁摄取行为，在这两种增强剂的范式中 同时可用。-3--4nAChR导向的配体仅在减少尼古丁自身 行政管理。这些初步发现使我们假设42 nAChRs可能是一个可行的靶点 开发治疗酒精依赖的药物疗法。为了验证这一假设，我们在这里建议使用 用于检测新的、高亲和力和选择性的42nAChR拮抗剂是否 有效减少酒精成瘾的重要方面，包括酒精摄入量过多和易受伤害 故态复萌。为实现这一目标，提出了两个具体目标。具体目标的目的1 是(A)重新合成选择性的_4-_2nAChR化合物(TPI-202、-211、-412和-421)和(B)在 体内试验前的体外功能活动。具体目标2旨在测试这些药物的体内疗效 化合物。这将确定选择性的42拮抗剂是否同时阻断(A)有效和过度 家庭笼子饮酒和(B)重新饮酒，根据线索诱导和压力评估- 诱导复职范式。我们期望这项多学科的提案将确定新的药理作用 这些工具可以在未来的第二阶段应用中进行优化，并最终用作 过度饮酒和依赖。

PROJECT SUMMARY Alcohol addiction and disorders associated to excessive alcohol use are a serious public health problem in the United States and in other parts of the world. Current pharmacotherapies for the treatment of these disorders show limited efficacy. Preclinical and clinical findings point to nicotinic acetylcholine receptors (nAChRs) as an alternative, promising target for the development of novel and effective medications. However, it is unclear which specific nAChR subtypes serve as mediators of the rewarding effects of alcohol due, in part, to the complexity of the different possible combinations of the subunits that compose nAChRs and the lack of potent and selective ligands. Using combinatorial libraries, scaffold ranking and position scanning strategies, Assuage Pharmaceuticals, in collaboration with Torrey Pines Institute for Molecular Studies has discovered new scaffolds that have produced high affinity nAChR antagonists with exquisite selectivity for 42 nAChRs over 34 nAChRs, with respect to both binding affinity and in vitro functional activity. When tested in rats, one lead compound, TPI-202 as well as varenicline (a partial agonist of 42 nAChRs), but not 34 nAChR directed ligands, attenuated both alcohol- and nicotine-taking behaviors in a paradigm in which the two reinforcers were concurrently available. The 34 nAChR directed ligands were only effective in reducing nicotine self- administration. These initial findings led us to hypothesize that 42 nAChRs may serve as a viable target for developing pharmacotherapies to treat alcohol dependence. To verify this hypothesis, here we propose to use the Assuage compounds to examine whether novel, high affinity and selective 42 nAChR antagonists are effective in reducing important aspects of alcohol addiction including excessive alcohol intake and vulnerability to relapse. To accomplish this objective two specific aims have been proposed. The purpose of Specific Aim 1 is to (A) re-synthesize selective 42 nAChR compounds (TPI-202, -211, -412, and -421) and (B) determine in vitro functional activities prior to in vivo testing. Specific Aim 2 is aimed at testing the in vivo efficacy of these compounds. It will determine whether the selective 42 antagonists block (A) both operant and excessive home cage alcohol drinking and (B) relapse into alcohol seeking as assessed by both cue-induced and stress- induced reinstatement paradigms. We expect this multidisciplinary proposal to identify novel pharmacological tools that can be optimized in a future Phase II application, and ultimately to be used as medications for excessive alcohol use and dependence.