HALLUCINOGENS ON 5-HT RECEPTORS: MECHANISMS/DRUG DEVLPMT

长期目标是重新调整对结构性基础的理解 迷幻剂对神经递质受体的作用 5-羟色胺(5-HT)，并设计具有选择性的新化合物 作为激动剂，部分激动剂和拮抗剂在受体上共享 迷幻剂和其他5-羟色胺受体配体。这类化合物应该 为调查致幻剂提供新的工具，并提供 对新的治疗和预防方式的承诺。这项建议 重点介绍5-HT1a和5-HT2受体。一种新的分子模型 5-HT1a受体的药理药效是由 受体识别和激活的特定分子机制。它 将使用一种大型化学物质的刺激进行校准和精炼 位于模型内的各种已知和可能的5-HT1a配体 初步研究中确定的受体蛋白。配基对蛋白质的影响 受体激活机制(质子转移)将通过以下方法进行评估 量子化学和分子动力学的计算方法。 结果将被用来定义疗效的分子相关性，这将 用于设计具有5-HT1a选择性的新分子结构 受体和预测的激动型活性程度。其有效性和有效性 此外，还将从理论上探讨这些关联式的适用性 试验性的(见下文)。遵循类似的协议， 5-HT2受体的识别和激活将基于 工作假说，药物在该受体的相互作用是 由芳香氨基酸的残留物堆积而成。短的 肽序列(例如，Arg-Phe-Ser-Trp、Trp-Ser-Tyr、Phe-Arg-Trp)来自 已知的结合5-羟色胺的蛋白质，包括髓鞘碱性蛋白、LHRH和MSH- ACTH将作为5-HT2选择性配体的第一个靶标模型。 基于模型受体蛋白的结论之间的关系 对于5-HT1a和5-HT2受体，以及涉及 真正的5-羟色胺受体，将被用来对抗氨基酸的推论 真品受体蛋白的序列。实验确定的 作用于两个5-羟色胺受体的化合物的药理学特征将 用于建立分子结构与药物之间的关系 功效。由其衍生物表示的化学类别中的化合物 吲哚、苯烷胺和麦角林将在#年在这些体系中进行研究。 与已知受体激动剂和拮抗剂的比较。化验 将包括：a)由偶联的5-HT1A受体介导的反应 大鼠海马腺苷环化酶I膜制剂，以及b) 5-HT2受体介导的兔离体主动脉收缩； 将获得独立的药物疗效衡量标准。中的更改 Ca~(2+)活化剂BAY K 8644药效与浓度的关系 它将明显的拮抗剂d-LSD转化为5-HT2激动剂 疗效，以及由此产生的结果也将得到评估。信号的调制 人脑和大鼠脑片上受体-G蛋白与激动剂的结合 相互作用将通过放射自显影实验进行研究。

The long term goal is to reline the understanding of the structural basis for the action of hallucinogens on receptors of the neurotransmitter serotonin (5-HT), and to design novel compounds with selective properties as agonists, partial agonists and antagonists on the receptors shared by hallucinogens and other 5-HT-receptor ligands. Such compounds should provide new tools for the investigation of hallucinogens, and offer the promise for new therapeutic and preventive modalities. The proposal focuses on the 5-HT1A and 5-HT2 receptors. A molecular model for pharmacological drug efficacy at 5-HT1A receptors was developed from specific molecular mechanisms of receptor recognition and activation. It will be calibrated and refined using stimulations of a large chemical variety of known an d putative 5-HT1A ligands positioned inside a model receptor protein identified in preliminary studies. Effects of ligands on the receptor activation mechanism (proton transfer) will be evaluated with the computational methods of quantum chemistry and molecular dynamics (MD). Results will be used to define molecular correlates of efficacy which will serve in the design of new molecular structures with selectivity for 5-HT1A receptors and predicted degrees of agonistic activity. The validity and applicability of the correlates will be probed theoretically as well as experimentally (see below). Following similar protocols, the elements of recognition and activation at 5-HT2 receptors will be defined based on the working hypothesis that the interaction of drugs at this receptor is governed by stacking with a residue of an aromatic amino acid. Short peptide sequences (e.g., Arg-Phe-Ser-Trp, Trp-Ser-Tyr, Phe-Arg-Trp) from proteins known to bind 5-HT, including myelin basic protein, LHRH and MSH- ACTH will serve as first models of targets for 5-HT2 selective ligands. The relationship between conclusions based on the model receptor proteins for both the 5-HT1A and the 5-HT2 receptors, and mechanisms involving the real 5HT-receptors, will be probed against inferences from the amino acid sequences of he authentic receptor proteins. Experimentally determined pharmacological profiles of compounds acting at the two 5-HT receptors will be used to establish the relation between molecular structure and drug efficacy. Compounds in the chemical classes represented by derivatives of indole, phenylalkylamine and ergoline, will be studied in these systems in comparison with known agonists and antagonists on the receptors. Assays will include: a) responses mediated by the 5-HT1A receptor coupled to adenylate cyclase i membrane preparations from rat hippocampus, and b) the contraction of the isolated rabbit aorta mediated by 5-HT2 receptors; independent measures of drug efficacy will be obtained. Changes in efficacy as function of concentration of the Ca2+ activator BAY K 8644 which converts an apparent antagonist, d-LSD, to a 5-HT2 agonist with low efficacy, and those resulting will also be evaluated. The modulation of agonist binding in human and rat brain sections by receptor-G protein interactions will be studied from autoradiography experiments.