Developmemt of Novel Treatments for Nicotine Addiction

描述（由申请人提供）：吸烟是头号健康问题，占更多的疾病和死亡在美国比任何其他因素。尽管目前的一些药物疗法（即，尼古丁替代品和安非他酮），复发率仍然很高，这表明需要新的药物。本申请中的研究提出开发一类新的亚型选择性烟碱受体（nAChR）拮抗剂作为对烟草使用停止和尼古丁依赖治疗有效的治疗剂。尽管烟草使用行为和尼古丁成瘾与抑郁症有关，但这些新型候选药物也可能被证明是治疗抑郁症的新方法。基于安非他酮作为nAChR拮抗剂和非选择性nAChR拮抗剂美加明作为烟草使用停止剂具有一定功效，但受到其外周介导的便秘副作用的限制的观察，我们预测我们建议开发的亚型选择性nAChR拮抗剂，在尼古丁成瘾的治疗中作为烟草使用停止剂可能具有治疗优势和功效。我们假设，用亲脂性N-取代基季铵化尼古丁分子的吡啶-N原子以提供N-烟碱类似物和/或通过用亲脂性接头连接这些季铵部分以提供N，N '-双类似物将产生亚型选择性nAChR拮抗剂，其将抑制尼古丁诱发的多巴胺、去甲肾上腺素或5-羟色胺释放，并因此抑制尼古丁诱导的行为，表明它们作为尼古丁成瘾治疗剂的潜力。还将评价主要候选药物的脑生物利用度、药代动力学和代谢。使用天然和重组nAChRs的结果比较将提供新的见解nAChRs介导这些功能的亚基组成。将评估候选药物减少尼古丁自我给药、减少尼古丁诱导的尼古丁寻求行为恢复以及促使尼古丁依赖动物戒断的能力。因此，一种综合方法（即，药物化学、药代动力学、代谢、药理学、心理学和神经科学）将用于增加我们对烟草使用和尼古丁成瘾的潜在机制的理解，重点是候选药物的开发。

DESCRIPTION (provided by applicant): Tobacco smoking is the number one health problem accounting for more illnesses and deaths in the US than any other factor. Despite efficacy of some current pharmacotherapies (i.e., nicotine replacement and bupropion), relapse rates continue to be high, indicating that novel medications are needed. Research in the current application proposes to develop a new class of subtype-selective nicotinic receptor (nAChR) antagonists as therapeutic agents with efficacy for tobacco use cessation and for treatment of nicotine dependence. As much as tobacco use behavior and nicotine addiction have links to depression, these novel drug candidates may also prove to be new treatments for depression. Based on the observations that the bupropion acts as a nAChR antagonist and that the nonselective nAChR antagonist, mecamylamine, has some efficacy as a tobacco use cessation agent, but is limited by its peripherally-mediated side-effect of constipation, we predict that the subtype-selective nAChR antagonists, which we propose to develop, may have therapeutic advantages and efficacy as tobacco use cessation agents in the treatment of nicotine addiction. We hypothesize that quaternizing the pyridine-N atom of the nicotine molecule with a lipophillic N-substituent to afford N-nicotinium analogs and/or by connecting these quaternary ammonium moieties with a lipophillic linker to afford N,N'-bis-analogs will result in subtype-selective nAChR antagonists, which will inhibit either nicotine-evoked dopamine, norepinephrine or serotonin release, and thus, inhibit nicotine-induced behaviors, indicating their potential as nicotine addiction treatments. Brain bioavailability, pharmacokinetics and metabolism of the lead candidates will also be evaluated. Comparison of results using native and recombinant nAChRs will provide new insights into the subunit composition of nAChRs mediating these functions. Drug candidates will be assessed for their ability to decrease nicotine self-administration, to decrease nicotine-induced reinstatement of nicotine seeking behavior, and to precipitate withdrawal in nicotine-dependent animals. Thus, an integrative approach (i.e., medicinal chemistry, pharmacokinetics, metabolism, pharmacology, psychology and neuroscience) will be used to increase our understanding of the underlying mechanisms of tobacco use and nicotine addiction, with focus on pharmacotherapeutic candidate development.