Developmemt of Novel Treatments for Nicotine Addiction

描述(申请人提供)：吸烟是头号健康问题，在美国，吸烟导致的疾病和死亡比其他任何因素都多。尽管目前的一些药物疗法(如尼古丁替代疗法和安非他酮)有效，但复发率仍然很高，这表明需要新的药物。目前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剂。尽管烟草使用行为和尼古丁成瘾与抑郁症有关，这些新的候选药物也可能被证明是治疗抑郁症的新疗法。根据安非他酮作为nAChR拮抗剂的作用以及非选择性nAChR拮抗剂甲氨基甲胺作为烟草戒除剂有一定的疗效，但受到其外周介导的便秘副作用的限制，我们预测我们建议开发的亚型选择性nAChR拮抗剂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，将尼古丁分子中的吡啶-N原子与脂基N-取代基季铵连接，得到N-烟碱类似物，和/或通过将这些季铵基团与脂基连接，得到N，N‘-双-类似物，将产生亚型选择性的nAChR拮抗剂，它将抑制尼古丁诱发的多巴胺、去甲肾上腺素或5-羟色胺的释放，从而抑制尼古丁诱导的行为，表明它们有可能作为尼古丁成瘾治疗药物。还将评估候选药物的脑生物利用度、药代动力学和新陈代谢。使用天然和重组nAChRs的结果的比较将为nAChRs的亚基组成提供新的见解，这些亚基介导这些功能。将评估候选药物在减少尼古丁自我给药、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方面的能力。因此，将使用一种综合的方法(即药物化学、药代动力学、新陈代谢、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，重点是开发药物治疗候选药物。

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.