Developmemt of Novel Treatments for Nicotine Addiction

描述（由申请人提供）：在美国，吸烟是头号健康问题，造成的疾病和死亡比任何其他因素都多。尽管目前的一些药物治疗（即尼古丁替代和安非他酮）有效，复发率仍然很高，这表明需要新的药物。当前应用的研究建议开发一类新的亚型选择性尼古丁受体（nAChR）拮抗剂，作为戒烟和治疗尼古丁依赖的有效治疗药物。就像烟草使用行为和尼古丁成瘾与抑郁症有关一样，这些新型候选药物也可能被证明是治疗抑郁症的新方法。基于观察到安非他酮作为nAChR拮抗剂和非选择性nAChR拮抗剂甲胺作为戒烟药物有一定疗效，但受其外周介导的便秘副作用的限制，我们预测，我们提出的亚型选择性nAChR拮抗剂作为戒烟药物在治疗尼古丁成瘾方面可能具有治疗优势和疗效。我们假设将尼古丁分子的吡啶-N原子与亲脂性N取代基季铵化以获得N-尼古丁类似物，或者通过将这些季铵部分与亲脂性连接剂连接以获得N，N'-双类似物，将产生亚型选择性nAChR拮抗剂，这些拮抗剂将抑制尼古丁引起的多巴胺，去甲肾上腺素或血清素的释放，从而抑制尼古丁诱导的行为，表明它们具有治疗尼古丁成瘾的潜力。脑生物利用度，药代动力学和代谢的主要候选人也将进行评估。使用天然和重组nAChRs的结果比较将为nAChRs亚基组成介导这些功能提供新的见解。候选药物将评估其减少尼古丁自我给药的能力，减少尼古丁诱导的尼古丁寻求行为的恢复，以及促使尼古丁依赖动物戒断的能力。因此，将采用综合方法（即药物化学，药代动力学，代谢，药理学，心理学和神经科学）来增加我们对烟草使用和尼古丁成瘾的潜在机制的理解，重点是药物治疗候选药物的开发。

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.