SELECTIVE SEROTONERGIC AGENTS

选择性血清素能药物

• 批准号: 6703087
• 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 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6703087
• 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）： 血清素（5-羟色胺；5-HT）受体与多种疾病有关 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。的多样性 这些影响至少可以部分地通过大量的 现已鉴定的 5-HT 受体群：5-HT1-5-HT7。许多 这七个种群已被证明由亚种群组成并且在 至少 20 个不同的 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能配体，这仅是推测。的确， 很少有真正的亚群选择性激动剂或拮抗剂 发达。本研究的目的是开发此类药物。 具体来说，我们建议 (a) 解释 5-HT2A 与 5-HT2C 的选择性 Spiperone 并开发和测试一个最终可能的综合模型 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 新鉴定的5-HT1F配体。 5-HT2A 拮抗剂可能具有非典型价值 抗精神病药，有证据表明 5-HT6 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-HT1F 受体可能在偏头痛中发挥作用。虽然可能有 开发此类药物的临床价值，其确切用途尚不清楚 此时。因此，该应用程序更直接的目标是开发 此类试剂作为进一步研究其药理意义的工具 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经确定，(a) 5-HT2A 与 5-HT2C 拮抗剂（即 KML-010），(b) 5-HT6 选择性 激动剂（即 2-MMT），以及 (c) 新型 5-HT1F 配体。 KML-010 的新类似物 将在放射性配体结合和行为研究中合成和检查 为了测试我们制定的假设模型来解释 螺哌隆对 5-HT2A 具有选择性，而酮舍林缺乏选择性。这 5-HT6 激动剂 2-MMT 尚未经过彻底研究，仅与 亲和力适中，可能难以穿透血脑 由于其化学成分而具有屏障作用。我们建议系统地利用 我们已经确定了其他线索，以尝试优化活动。 将进行放射性配体结合和功能测定。 5-HT1F配体 没有选择性；我们建议探索其结构-活性关系 和功能活性，试图开发 5-HT1F 选择性配体。

项目成果

Interaction of N1-unsubstituted and N1-benzenesulfonyltryptamines at h5-HT6 receptors.

N1-未取代和 N1-苯磺酰色胺在 h5-HT6 受体上的相互作用。

• DOI: 10.1016/j.bmcl.2006.08.068
• 发表时间: 2006
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Kolanos,Renata;Dukat,Malgorzata;Roth,BryanL;Glennon,RichardA
• 通讯作者: Glennon,RichardA

Possible differences in modes of agonist and antagonist binding at human 5-HT6 receptors.

人类 5-HT6 受体激动剂和拮抗剂结合模式可能存在差异。

• DOI: 10.1016/j.bmcl.2004.05.076
• 发表时间: 2004
• 期刊: Bioorganic & medicinal chemistry letters.
• 作者: Pullagurla,ManikR;Westkaemper,RichardB;Glennon,RichardA
• 通讯作者: Glennon,RichardA

Binding of sulfonyl-containing arylalkylamines at human 5-HT6 serotonin receptors.

• DOI: 10.1021/jm060469q
• 发表时间: 2006-07
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: D. Sikazwe;M. Bondarev;M. Dukat;J. B. Rangisetty;B. Roth;R. Glennon

1,2,3,4-tetrahydrocarbazoles as 5-HT6 serotonin receptor ligands.

1,2,3,4-四氢咔唑作为 5-HT6 血清素受体配体。

• DOI: 10.1016/j.bmcl.2004.01.071
• 发表时间: 2004
• 期刊: Bioorganic & medicinal chemistry letters.
• 作者: Chang-Fong,Jean;Rangisetty,JagadeeshB;Dukat,Malgorzata;Setola,Vincent;Raffay,Thomas;Roth,Bryan;Glennon,RichardA
• 通讯作者: Glennon,RichardA

N1-benzenesulfonylgramine and N1-benzenesulfonylskatole: novel 5-HT6 receptor ligand templates.

N1-苯磺酰麦胺和 N1-苯磺酰粪臭素：新型 5-HT6 受体配体模板。

• DOI: 10.1016/s0960-894x(03)00612-7
• 发表时间: 2003
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Pullagurla,ManikR;Dukat,Małgorzata;Setola,Vincent;Roth,Bryan;Glennon,RichardA
• 通讯作者: Glennon,RichardA