Discovery of alpha4beta2 Nicotinic Receptor Antagonists as Alcohol Abuse Medications

项目摘要 酒精成瘾和与过度饮酒有关的疾病是美国一个严重的公共卫生问题。 美国和世界其他地区。目前用于治疗这些疾病的药物疗法 显示出有限的功效。临床前和临床研究结果指出，烟碱乙酰胆碱受体（nAChRs）作为一种 替代的，有前途的目标，为发展新的和有效的药物。但目前尚不清楚 哪些特定的nAChR亚型作为酒精奖励效应的介质，部分原因是 组成nAChR的亚基的不同可能组合的复杂性和缺乏有效的 和选择性配体。使用组合文库、支架排序和位置扫描策略， 制药公司与Torrey Pines分子研究所合作， 支架已经产生了高亲和力的nAChR拮抗剂，对nAChR具有精确的选择性， 在结合亲和力和体外功能活性方面，在老鼠身上测试时， 化合物TPI-202以及伐尼克兰（α 4 β 2 nAChR的部分激动剂），但不是α 3 β 4 nAChR定向的 配体，减弱了酒精和尼古丁的摄入行为，在一个范例中，这两种抑制剂是 同时可用。靶向nAChR的配体仅在降低尼古丁自身代谢方面有效。 局这些初步的发现使我们假设nAChRs可能作为一个可行的靶点， 开发药物治疗酒精依赖。为了验证这一假设，我们建议使用 本发明的化合物用于检测是否存在新的、高亲和力和选择性的α 4 β 2 nAChR拮抗剂， 有效减少酒精成瘾的重要方面，包括过量饮酒和脆弱性 复发为实现这一目标，提出了两个具体目标。具体目标1 是（A）重新合成选择性β 4 β 2 nAChR化合物（TPI-202、-211、-412和-421）和（B）， 在体内测试之前进行体外功能活性。具体目标2旨在测试这些化合物的体内功效。 化合物.它将确定选择性β 4 β 2拮抗剂是否阻断（A）操作性和过度的 家庭笼饮酒和（B）复发到酒精寻求，如通过线索诱导和压力两者评估的。 诱导恢复范式。我们希望这一多学科的建议，以确定新的药理学 这些工具可以在未来的第二阶段应用中进行优化，并最终用作药物， 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.