Development of Ligands for Nicotinic Receptors

描述（由申请人提供）：拟议研究的长期目标是开发潜在的治疗尼古丁成瘾的药物。我们的第一个策略是开发部分激动剂和拮抗剂，作用于烟碱受体的正构位。我们的第二个策略是开发尼古丁受体的负变构调节剂，它可能提供不同于正构配体的药理学特征。我们发现PCP（非nmda）第二位点的配体在烟碱受体上起负变构调节剂的作用，这是我们提出六氢茚[1,2]-吡咯、四氢-2,5-甲烷- 2h -苯氮平和四氢-2,5-甲烷- 1h -2-苯氮平类似物的合成和评价方案的基础。本项目的假设是，成功的戒烟药物治疗至少包括对a4b2 nAChR亚型的部分激活或阻断作用（直接或间接）。正构合成计划的目标是开发具有广泛功效的类似物，包括部分激动剂到纯拮抗剂。我们的一般方法是合成并评估依比替丁类似物与[3H]依比替丁（a4b2* like-nAChR）和[125I]碘- mla结合（a7 like-nAChR）在大鼠脑中的竞争能力。符合标准的类似物将在小鼠体内进行评估，而那些表现出特定标准的类似物将在物理戒断和奖励模型（条件位置偏好和自我给药）中进一步评估。选择的类似物将在大鼠自我给药模型中进行评估。有趣的类似物将在卵母细胞中评估各种nachr的受体功效和选择性。由于变构调节剂不会与[3H]依比替丁和[125I]碘- mla结合直接竞争，因此需要稍作修改的方法。相反，我们将首先评估它们在含有a4b2、a3b4和a7 nachr的卵母细胞中改变乙酰胆碱作用的能力。竞争性修正：不可能用许多先前研究过的化合物的体外nAChR结合和功效测定结果来解释各种体内试验的药理学结果。该补充是为了扩大我们的研究范围，通过开发a6b2* nAChR多巴胺释放功效试验，并评估许多先前制备的化合物和该a6b2*试验中的所有新目标化合物。这些结果将使我们能够更好地解释以前研究过的化合物的一些体内结果，并更好地优先考虑未来体内研究的新化合物。如果我们的研究范围的扩大导致有效的和选择性的a6b2* nAChR配体，这些新的配体将是一个有价值的药理学工具，不仅对我们的研究，而且对其他研究nAChR的研究者也是如此。

DESCRIPTION (provided by applicant): The long-range goal of the proposed research is to develop potential treatment medications for nicotine addiction. Our first strategy is to develop partial agonists and antagonists that act at the orthosteric site of nicotinic receptors. Our second strategy is to develop negative allosteric modulators for nicotinic receptors that may provide a pharmacological profile different from that of orthosteric ligands. Our discovery that ligands for the PCP (non-NMDA) second site acted as negative allosteric modulators at nicotinic receptors served as the basis for proposing a synthetic and evaluation program for hexahydroindeno[1,2]- pyrrole, tetrahydro-2,5-methano-2H-benzazepine, and tetrahydro-2,5-methano-1H-2-benzazepine analogs. This project's hypothesis is that a successful smoking cessation pharmacotherapy would at least include partial activating or blocking action (direct or indirect) at a4b2 nAChR subtypes. The orthosteric synthetic pro- gram's goal is to develop analogs with a wide range of efficacies to include partial agonists to pure antagonists. Our general approach will be to synthesize and evaluate epibatidine analogs for their ability to compete with [3H]epibatidine (a4b2* like-nAChR) and [125I]iodo-MLA binding (a7 like-nAChR) in rat brain. Analogs meeting criteria will be evaluated in vivo in a mouse, and those exhibiting specific criteria will be evaluated further in physical withdrawal and reward models (conditioned place preference and self-administration). Selected analogs will be evaluated in rat self-administration models. Interesting analogs will be evaluated in oocytes for receptor efficacy and selectivity at various nAChRs. A slightly modified approach will be required for allosteric modulators since they will not compete directly with [3H]epibatidine and [125I]iodo-MLA binding. Rather, they will be evaluated initially for their ability to alter ACh effects in oocytes containing a4b2, a3b4, and a7 nAChRs. Competitive Revision: It has not been possible to explain the pharmacological results from the various in vivo tests with the results obtained from the in vitro nAChR binding and efficacy assay results of many previously studied compounds. This supplement is to increase the scope of our studies by developing an a6b2* nAChR dopamine release efficacy assay and evaluating a number of previously prepared compounds and all new target compounds in this a6b2* assay. The results will allow us to better explain some of the in vivo results from previously studied compounds and to better prioritize new compounds for in vivo studies in the future. If this increase in the scope of our studies leads to potent and selective a6b2* nAChR ligands, these new ligands will be a valuable pharmacological tool not only for our research but that of other investigators studying the nAChRs as well. PUBLIC HEALTH RELEVANCE: In 2004, an estimated 46 million Americans were cigarette smokers. Even though most smokers want to quit, only about 3% can do so without the use of other intervention. Since smoking is associated with cancer, cardiovascular disease, cerebral vascular disease, chronic obstructive airway disease, and pregnancy complications, development of new and better pharmacotherapies to treat smokers would be tremendously beneficial to society. This application addresses this problem by proposing studies to develop competitive antagonists and partial agonists as well as allosteric modulators of nicotinic acetylcholine receptors as new pharmacotherapies to treat smokers.