Development of Ligands for Nicotinic Receptors

烟碱受体配体的开发

• 批准号: 7901683
• 负责人: FRANK Ivy CARROLL
• 金额: $ 42.62万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-05 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901683
• 关键词: Acute; Address; Affective; Affinity; Agonist; American; Animal Model; Animals; Behavior; Behavioral; Benzazepines; Binding; Biological Assay; Brain; Cardiovascular Diseases; Cerebrum; Chronic; Chronic Obstructive Airway Disease; Cigarette Smoker; Dependence; Development; Effectiveness; Evaluation; Exhibits; Exposure to; Goals; Grant; In Vitro; Individual; Intervention; Label; Lead; Ligands; Malignant Neoplasms; Measures; Methods; Modeling; Modification; Motor Activity; Mus; Neurons; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nicotinic Receptors; Oocytes; Pharmaceutical Preparations; Pharmacotherapy; Phencyclidine; Physiological; Pregnancy Complications; Program Evaluation; Property; Pyrroles; Rattus; Research; Research Institute; Rewards; Role; Self Administration; Series; Site; Smoke; Smoker; Smoking; Societies; Specificity; System; Testing; Tobacco; Universities; Vascular Diseases; Virginia; Withdrawal; Xenopus oocyte; addiction; analog; base; design; epibatidine; experience; in vivo; insight; interest; meetings; mouse model; natural hypothermia; novel; novel therapeutics; preference; programs; public health relevance; pyridine; radioligand; receptor; smoking cessation; tool

DESCRIPTION (provided by applicant): It is now well established that the addiction experienced by smokers is due to the nicotine present in the tobacco. Nicotine produces a myriad of profound behavioral and physiological effects. It is acutely rewarding, which promotes repeated drug administration and could lead to dependence in vulnerable individuals. Nicotine reinforces self-administration and reinforces place preference in animals. In addition, cessation of chronic exposure to nicotine results in withdrawal that consists of somatic and affective components. 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 progress to date has demonstrated that epibatidine analogs hold great promise in that specific structural modifications have resulted in analogs with extremely high affinity for receptors labeled with [3H]epibatidine but with varying degrees of efficacy. 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. The hypothesis of this project is that a successful smoking cessation pharmacotherapy would at least include partial activating or blocking action (direct or indirect) at orthosteric synthetic program 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 the epibatidine analogs for their ability to compete with [3H]epibatidine ( brain. Analogs meeting criteria will be evaluated in vivo in a mouse model (acute agonist and antagonist properties), and those that exhibit specific criteria will be evaluated further in physical withdrawal and reward models (conditioned place preference and self-administration). Plans are underway to begin testing analogs already identified as lead compounds in rat self-administration. Analogs of interest will be evaluated in oocytes for receptor efficacy and selectivity at various nAChRs. A slightly modified approach will be required for the 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 42, 34, and 7 nAChRs. Those that are identified as negative modulators will be candidates for in vivo evaluation. 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）：现在已经很好地确定，吸烟者所经历的成瘾是由于烟草中存在的尼古丁所致。尼古丁产生无数的深刻行为和生理影响。它是非常有益的，它促进了重复的药物管理，并可能导致弱势群体的依赖。尼古丁加强自我管理并增强动物的偏好。此外，停止长期暴露于尼古丁会导致戒断，由躯体和情感成分组成。拟议的研究的远程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在烟碱受体正常部位作用的部分激动剂和拮抗剂。我们迄今为止的进步表明，表育生类似物具有很大的希望，因为特定的结构修饰导致对标记为[3H] epibatidine标记的受体的类似物具有很高的亲和力，但功效程度不同。我们的第二个策略是为烟碱受体开发负面的变构调节剂，这些调节剂可能提供的药理学特征与正常人配体不同。我们发现，烟碱受体对PCP（非NMDA）第二个位点的配体作为负的变构调节剂，作为提出己二氢[1,2]吡咯[1,2]的合成和评估程序的基础类似物。该项目的假设是，在正前置合成计划中，成功的戒烟药物治疗至少包括部分激活或阻止作用（直接或间接），以开发具有广泛效率的类似物，以包括对纯拮抗剂的部分激动剂。我们的一般方法将是合成和评估表皮定类似物的能力，以与[3H] EpibaTidine竞争（大脑。类似于符合标准的类似物，将在鼠标模型（急性激动剂和拮抗剂属性）中在体内进行评估，并在有条件的验证模型中进一步评估了特定标准的验证和奖励模型（并在奖励模型中进行了进一步评估），并进行了自我奖励（有条件的奖励）。在卵母细胞中，在各种NACHR中，将对卵母细胞进行识别为大鼠的类似物。含有42、34和7个nACHR的卵母细胞将是体内评估的候选者。公共卫生相关性：2004年，估计有4600万美国人吸烟者。即使大多数吸烟者都想戒烟，但只有大约3％的人可以在不使用其他干预措施的情况下这样做。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以及妊娠并发症有关，因此开发新的，更好的药物治疗吸烟者将对社会产生极大的利益。该申请通过提出研究来开发竞争性拮抗剂和部分激动剂以及烟碱乙酰胆碱受体的变构调节剂来解决此问题，作为治疗吸烟者的新药物治疗。