HALLUCINOGENS ON 5-HT RECEPTORS: MECHANISMS/DRUG DEVLPMT

长期目标是重新认识结构基础 致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 作为受体的激动剂、部分激动剂和拮抗剂， 致幻剂和其他5-HT受体配体。 这些化合物应 为研究致幻剂提供了新的工具， 新的治疗和预防方法的希望。 该提案 主要研究5-HT 1A和5-HT 2受体。 一个分子模型， 5-HT 1A受体的药理学药物功效是从 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来校准和改进 各种已知和假定的5-HT 1A配体位于模型内 在初步研究中鉴定的受体蛋白。 配体对 受体活化机制（质子转移）将用 量子化学和分子动力学的计算方法。 结果将用于定义功效的分子相关性，这将 用于设计对5-HT 1A具有选择性的新分子结构 受体和预测的激动活性程度。 的有效性和 相关的适用性将从理论上探讨，以及 实验（见下文）。 遵循类似的协议， 5-HT 2受体的识别和激活将基于 工作假设药物在该受体上的相互作用是 由芳香族氨基酸残基堆积控制。 短 肽序列（例如，Arg-Phe-Ser-Trp、Trp-Ser-Tyr、Phe-Arg-Trp）， 已知结合5-HT的蛋白质，包括髓鞘碱性蛋白、LHRH和MSH- ACTH将作为5-HT 2选择性配体的第一个靶点模型。 基于模型受体蛋白的结论之间的关系 5-HT 1A和5-HT 2受体，以及涉及 真实的5-HT受体，将被探测反对推论从氨基酸 真实受体蛋白的序列。 实验确定 作用于两种5-HT受体的化合物的药理学特性将 用于建立分子结构与药物之间的关系 功效 以下列化合物的衍生物为代表的化学类别中的化合物： 吲哚，苯基烷基胺和麦角林，将在这些系统中进行研究， 与已知的受体激动剂和拮抗剂的比较。 测定 a）由5-HT 1A受体介导的反应， 来自大鼠海马的腺苷酸环化酶i膜制备物，和B） 5-HT_2受体介导的离体兔主动脉收缩; 将获得药物功效的独立测量。 变化 作为Ca 2+激活剂BAY K 8644浓度的函数的功效 它将明显的拮抗剂d-LSD转化为低浓度的5-HT 2激动剂 疗效，并将评估结果。 的调制 受体-G蛋白在人和大鼠脑切片中的激动剂结合 将通过放射自显影实验研究相互作用。

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.