SELECTIVE SEROTONERGIC AGENTS

选择性血清素能药物

• 批准号: 6266922
• 负责人: RICHARD A GLENNON
• 金额: $ 27.08万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-15 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6266922
• 关键词: antipsychotic agents; computer simulation; drug design /synthesis /production; inhibitor /antagonist; ketanserin; neurochemistry; neuropharmacology; protein structure function; radiotracer; receptor binding; serotonin receptor

DESCRIPTION(Adapted from applicant's abstract): Serotonin (5-hydroxytryptamine; 5-HT) receptors have been implicated in a wide variety of neuropsychiatric disorders including schizophrenia, depression, anxiety, obsessive-compulsive behavior, and panic disorders. The diversity of these implications can be explained, at least in part, by the large number of 5-HT receptor populations that now have been identified: 5-HT1-5-HT7. Many of these seven populations have been shown to consist of subpopulations and at least 20 different subpopulations and splice variants of 5-HT receptors have been cloned. In some instances, the exact role(s) of these 5-HT populations is merely speculative due to the lack of selective sertonergic ligands. Indeed, very few truly subpopulation-selective agonists or antagonists have been developed. The purpose of the present investigation is to develop such agents. Specifically, we propose (a) to explain the 5-HT2A versus 5-HT2C selectivity of spiperone and to develop and test a comprehensive model that might eventually allow the de novo design and synthesis of novel 5-HT2A antagonists, (b) to exploit the first example of a 5-HT6-selective agonist, and (c) to explore a newly identified 5-HT1F ligand. 5-HT2A antagonists may be of value as atypical antipsychotics, there is evidence that 5-HT6 receptors may be involved in psychosis, depression, and mood disorders, and preliminary findings suggest that 5-HT1F receptors may play a role in migraine. Although there may be clinical value in developing such agents, their exact utility is far from clear at this time. Hence, a more immediate goal of this application is to develop such agents as tools to further investigate the pharmacologic significance of these receptor populations and to study basic neurochemical mechanisms. We have already identified in the course of our preliminary investigations, (a) a 5-HT2A versus 5-HT2C antagonist (i.e., KML-010), (b) a 5-HT6-selective agonist (i.e., 2-MMT), and (c) a novel 5-HT1F ligand. New analogs of KML-010 will be synthesized and examined in radioligand binding and behavioral studies in order to test a hypothetical model we have formulated to account for the 5-HT2A selectivity of spiperone and the lack of selectivity of ketanserin. The 5-HT6 agonist 2-MMT has not been thoroughly investigated, binds only with modest affinity, and likely will have difficulty in penetrating the blood-brain barrier due to its chemical composition. We propose to systematically exploit additional leads we have already identified in an attempt to optimize activity. Radioligand binding and functional assays will be conducted. The 5-HT1F ligand is not selective; we propose to explore its structure-activity relationships and functional activity in an attempt to develop a 5-HT1F-selective ligand.

描述（改编自申请人摘要）： 5-羟色胺（5-hydroxytryptamine; 5-HT）受体与广泛的 各种神经精神疾病，包括精神分裂症，抑郁症， 焦虑、强迫行为和恐慌症。之多样 这些影响至少可以部分地由大量的 5-HT受体群现在已经确定：5-HT 1 -5-HT 7。许多 这七个种群已被证明是由亚群组成的， 至少有20种不同的5-HT受体亚群和剪接变体， 被克隆了在某些情况下，这些5-HT群体的确切作用是 由于缺乏选择性血清素能配体，这仅仅是推测性的。的确， 很少有真正的亚群选择性激动剂或拮抗剂被 开发本研究的目的是开发此类制剂。 具体地，我们提出（a）解释5-HT 2A对5-HT 2C的选择性， 并开发和测试一个全面的模型， 允许从头设计和合成新的5-HT 2 A拮抗剂，（B）， 利用5-HT 6选择性激动剂的第一个例子，和（c）探索 新发现的5-HT 1F配体。5-HT 2A拮抗剂可能具有非典型性 抗精神病药，有证据表明，5-HT 6受体可能参与 精神病，抑郁症和情绪障碍，初步研究结果表明， 5-HT 1F受体可能在偏头痛中起作用。尽管可能存在 在开发这种药物的临床价值方面，它们的确切用途还远不清楚 在这个时候因此，该应用程序的一个更直接的目标是开发 这些药物作为工具，以进一步研究药理学意义， 这些受体群体和研究基本的神经化学机制。 我们在初步调查过程中已确定，（a） 5-HT 2A对5-HT 2C拮抗剂（即，KML-010），（B）5-HT 6选择性 激动剂（即，2-MMT），和（c）新型5-HT 1F配体。KML-010的新类似物 将合成并在放射性配体结合和行为研究中进行检查 为了测试我们制定的假设模型， 螺哌隆的5-HT 2A选择性和酮色林的缺乏选择性。的 5-HT 6激动剂2-MMT尚未得到彻底研究，仅与 适度的亲和力，并且可能难以穿透血脑 这是由于其化学成分。我们建议系统地利用 我们已经确定的其他线索，以优化活动。 将进行放射性配体结合和功能测定。5-HT 1F配体 不是选择性的，我们建议探索其结构-活性关系 和功能活性，试图开发5-HT 1F-选择性配体。