Stereochemical Aspects of Hallucinogenesis

幻觉的立体化学方面

基本信息

批准号：
7668888
负责人：
DAVID E NICHOLS
金额：
$ 22.71万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-07-15 至 2010-09-14
项目状态：
已结题

项目摘要

Description This is a multidisciplinary proposal to continue our efforts to understand the structure-activity relationships of hallucinogens: drugs that are agonists at the serotonin 5-HT2A receptor. The work involves computer-assisted ligand design and receptor docking studies, both in vitro and in vivo pharmacology, and molecular biology methods. Aims in this application include an emphasis on the pharmacology and structure-activity relationships of LSD. There is an incomplete understanding of the factors that contribute to the uniquely high potency of LSD, and we propose several approaches to identify them. This effort will involve the synthesis and evaluation of several LSD analogues. We also have shown that the behavioral effects of LSD in rats occur in two temporal phases, and we will complete the synthesis of the 13-OH metabolite of LSD and assess its pharmacology and physiological relevance to these phases. We also shall continue efforts to characterize the basis for the behavioral changes induced by chronic LSD, and to search for targets other than the 5-HT2A receptor that may be important to the action of LSD. Aim 2 is focused on developing improved homology models of the human 5- HT2A receptor, starting with the crystal structure of the ¿2-adrenergic receptor. We shall have a focus on modeling extracellular loop 2, but also propose to examine the role of residue 3.36 in helix 3, as well as a previously-unrecognized disulfide linkage in extracellular loop 3. Computational approaches will be complemented by mutagenesis of loop residues and the use of stereochemically-defined lysergic acid amides. A third aim proposes new agonist ligands that should have high affinity for the 5-HT2A receptor, but which should possess low affinity for the 5-HT2C receptor, based on an improved strategy from our molecular modeling efforts.

描述这是一项多学科的建议，旨在继续我们的努力，以了解致幻剂：在5-羟色胺5-HT2A受体的激动剂的药物。这项工作涉及计算机辅助体外和体内药理学以及分子生物学的配体设计和受体对接研究方法。该应用中的目的包括强调药理学和结构活性关系 LSD。对导致高度高效力的因素有一个不完全理解 LSD，我们提出了几种识别它们的方法。这项工作将涉及综合和评估在几个LSD类似物中。我们还表明，LSD在大鼠的行为效应发生在两个临时阶段，我们将完成LSD的13-OH代谢物的合成，并评估其药理学和与这些阶段的生理相关性。我们还将继续努力来表征慢性LSD引起的行为变化，并搜索5-HT2A受体以外的其他目标对LSD的作用很重要。 AIM 2的重点是开发人类的改进同源模型5- HT2A受体，从2-肾上腺素受体的晶体结构开始。我们将关注对细胞外环2进行建模，但也建议研究住所3.36在Helix 3中的作用，以及一个以前未经公认的细胞外环3中的二硫键3。计算方法将是通过循环保留的诱变和立体定义定义的脂肪酸酰胺的使用完成。第三个目的提出了对5-HT2A受体具有很高亲和力的新激动剂配体的建议，但应基于我们分子的改进策略对5-HT2C受体的潜在低亲和力建模工作。