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尼古丁成瘾的潜在治疗药物。我们的第一个策略是开发作用于烟碱受体正构位点的部分激动剂和拮抗剂。我们的第二个策略是开发烟碱受体的负变构调节剂，其可以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，这一发现为提出六氢茚并[1，2]-吡咯、四氢-2，5-亚甲基-2H-苯并氮杂卓和四氢-2，5-亚甲基-1H-2-苯并氮杂卓类似物的合成和评价方案奠定了基础。 该项目的假设是，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）。正构合成程序的目标是开发具有广泛功效的类似物，包括纯拮抗剂的部分激动剂。我们的一般方法将是合成和评估地棘蛙素类似物在大鼠脑中与[3H]地棘蛙素（a4b2 * like-nAChR）和[125I]碘-MLA结合（a7 like-nAChR）竞争的能力。将在小鼠体内评价符合标准的类似物，并将在身体退缩和奖励模型（条件性位置偏好和自我给药）中进一步评价表现出特定标准的类似物。将在大鼠自我给药模型中评价选定的类似物。将在卵母细胞中评估感兴趣的类似物在各种nAChR的受体功效和选择性。对于变构调节剂，需要稍微修改的方法，因为它们不会直接与[3H]地棘蛙素和[125 I]碘-MLA结合竞争。相反，最初将评估它们在含有a4b2、a3b4和a7 nAChR的卵母细胞中改变ACh效应的能力。 竞争版本：用许多先前研究的化合物的体外nAChR结合和功效测定结果获得的结果无法解释各种体内试验的药理学结果。本补充旨在通过开发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本a6b2 * 试验中的所有新目标化合物来增加我们研究的范围。这些结果将使我们能够更好地解释以前研究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增加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，但其他研究人员研究的nAChR以及。 公共卫生相关性：2004年，估计有4600万美国人吸烟。尽管大多数吸烟者想要戒烟，但只有约3%的人可以在不使用其他干预措施的情况下戒烟。由于吸烟与癌症、心血管疾病、脑血管疾病、慢性阻塞性气道疾病和妊娠并发症有关，因此开发新的和更好的药物治疗吸烟者将对社会产生巨大的益处。本申请通过提出研究开发烟碱乙酰胆碱受体的竞争性拮抗剂和部分激动剂以及变构调节剂作为治疗吸烟者的新药物疗法来解决这个问题。

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.