Development of Ligands for Nicotinic Receptors

烟碱受体配体的开发

• 批准号: 7810119
• 负责人: FRANK Ivy CARROLL
• 金额: $ 21.22万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7810119
• 关键词: Acute; Address; Affinity; Agonist; American; Animal Model; Behavior; Benzazepines; Binding; Biological Assay; Brain; Cardiovascular Diseases; Cerebrum; Chronic Obstructive Airway Disease; Cigarette Smoker; Development; Dopamine; Exhibits; Future; Goals; In Vitro; Intervention; Ligands; Malignant Neoplasms; Measures; Methods; Modeling; Motor Activity; Mus; Neurons; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nicotinic Receptors; Oocytes; Pharmaceutical Preparations; Pharmacotherapy; Pregnancy Complications; Program Evaluation; Property; Pyrroles; Rattus; Reading; Research; Research Personnel; Rewards; Self Administration; Series; Site; Smoker; Smoking; Societies; System; Testing; Vascular Diseases; Withdrawal; Xenopus oocyte; addiction; analog; base; design; epibatidine; in vivo; interest; meetings; mouse model; natural hypothermia; novel; preference; public health relevance; radioligand; receptor; receptor binding; smoking cessation; tool

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.

描述（由申请人提供）：拟议研究的长期目标是开发治疗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，其可能提供与正构配体不同的药理学特征。我们发现 PCP（非 NMDA）第二位点的配体可作为烟碱受体的负变构调节剂，这一发现为提出六氢茚并[1,2]-吡咯、四氢-2,5-亚甲基-2H-苯并氮杂卓的合成和评估计划奠定了基础。 四氢-2,5-亚甲基-1H-2-苯并氮杂类似物。 该项目的假设是，成功的戒烟药物疗法至少包括对 a4b2 nAChR 亚型的部分激活或阻断作用（直接或间接）。正位合成计划的目标是开发具有广泛功效的类似物，包括部分激动剂和纯拮抗剂。我们的一般方法是合成并评估皮巴替丁类似物在大鼠脑中与 [3H]epibatidine (a4b2* like-nAChR) 和 [125I]iodo-MLA 结合 (a7 like-nAChR) 竞争的能力。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身体戒断和奖励模型（条件性位置偏好和自我给药）中进一步评估。选定的类似物将在大鼠自我给药模型中进行评估。将在卵母细胞中评估有趣的类似物对各种 nAChR 的受体功效和选择性。变构调节剂需要稍微修改的方法，因为它们不会直接与[3H]epibatidine 和[125I]iodo-MLA 结合竞争。相反，最初将评估它们改变含有 a4b2、a3b4 和 a7 nAChR 的卵母细胞中 ACh 效应的能力。 竞争性修订：无法用许多先前研究的化合物的体外 nAChR 结合和功效测定结果来解释各种体内测试的药理学结果。本补充文件旨在通过开发 a6b2* nAChR 多巴胺释放功效测定并评估该 a6b2* 测定中的许多先前制备的化合物和所有新目标化合物来扩大我们的研究范围。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。如果我们研究范围的扩大能够产生有效且选择性的 a6b2* nAChR 配体，那么这些新配体不仅对于我们的研究，而且对于其他研究 nAChR 的研究人员来说都将是一个有价值的药理学工具。 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% 的人能够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、更好的药物疗法来治疗吸烟者将对社会非常有益。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。