SELECTIVE SEROTONERGIC AGENTS

选择性血清素能药物

• 批准号: 6629270
• 负责人: RICHARD A GLENNON
• 金额: $ 25.95万
• 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/6629270
• 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(改编自申请人的摘要)： 5-羟色胺(5-羟色胺；5-羟色胺)受体参与了广泛的 各种神经精神障碍，包括精神分裂症，抑郁症， 焦虑症、强迫症和恐慌症。的多样性 这些影响可以解释，至少部分可以解释为 现已鉴定的5-羟色胺受体亚群：5-HT1-5-HT7。许多. 这七个种群已被证明由亚种群和 至少20个不同的5-羟色胺受体亚群和剪接变体 都被克隆了。在某些情况下，这些5-羟色胺群体的确切作用(S)是 由于缺乏选择性的血清能配体，这仅仅是推测。的确， 很少有真正的亚群选择性激动剂或拮抗剂是 发展起来的。本次调查的目的就是开发这类药物。 具体地说，我们建议(A)解释5-HT2A与5-HT2C的选择性 并开发和测试一个全面的模型，最终可能 允许从头设计和合成新型5-HT2A拮抗剂，(B) 利用5-HT6选择性激动剂的第一个例子，以及(C)探索一种 新鉴定的5-HT1F配体。5-HT2A拮抗剂可能是非典型的有价值的 抗精神病药物，有证据表明5-HT6受体可能参与了 精神病、抑郁症和情绪障碍，初步研究结果表明 5-HT1F受体可能在偏头痛中起作用。尽管可能会有 开发这类药物的临床价值，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 作为进一步研究其药理学意义的工具的药物 这些受体群体，并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-HT2A与5-HT2C拮抗剂(即KML-010)，(B)5-HT6选择性 激动剂(即2-MMT)和(C)新的5-HT1F配体。KML-010的新类似物 将被合成并在放射性配基结合和行为研究中进行检测 为了测试一个假设的模型，我们制定了一个模型来解释 螺环酮的5-HT2a选择性和酮丝氨酸的缺乏选择性。这个 5-HT6激动剂2-MMT尚未得到彻底研究，仅与 亲和力适中，很可能很难穿透血脑 由于它的化学成分，它是一种屏障。我们建议系统地利用 我们已经确定了更多线索，试图优化活动。 将进行放射性配基结合和功能分析。5-羟色胺1F配体 不是选择性的；我们建议探索它的结构-活性关系 和功能活性，试图开发5-HT1F选择性配体。