STEREOCHEMICAL ASPECTS OF HALLUCINOGENESIS

致幻剂的立体化学方面

基本信息

批准号：
7255820
负责人：
DAVID E NICHOLS
金额：
$ 31.56万
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 2008-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7255820
关键词：
3-Dimensional Address Affinity Agonist Alanine Antipsychotic Agents Attenuated Binding Binding Sites Biological Assay Build-it Cells Chronic Computer Assisted Computers Docking Dopamine Drug Design Funding Goals HTR2A gene Hallucinogens Homology Modeling Human Hydrogen Bonding In Vitro Intoxication Investigation Knowledge Laboratories Lead Libraries Ligand Binding Domain Ligands Light Link Location Mediating Methods Minor Modeling Molecular Molecular Biology Molecular Conformation Mutation Nature Numbers Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phase Phenethylamine Phenethylamines Rattus Receptor Activation Schizophrenia Series Serine Serotonin Serotonin Receptor 5-HT1A Serotonin Receptor 5-HT2A Side Site-Directed Mutagenesis Structure-Activity Relationship Techniques Work analog base behavioral sensitization design dopamine system in vivo model development mutant novel receptor

项目摘要

DESCRIPTION (provided by applicant): This is a highly interdisciplinary proposal to continue our efforts to understand the structure-activity relationships of hallucinogens: drugs that are agonists at the serotonin 5-HT2A receptor. It involves computer-assisted ligand design and receptor docking studies, in vitro and in vivo pharmacology, and molecular biology methods. More specifically, it builds on a recent homology model of the serotonin 5-HT2A receptor that we have developed in our laboratory, and proposes a number of specific mutations within the putative ligand binding domain. These mutations will be combined with pharmacological assessment of small agonist ligands to be synthesized or already in our extensive library, in order to examine functional complementation of binding and activation, the most powerful technique presently available for identification of direct ligand contacts within a receptor. Conformationally-constrained phenethylamine ligands also have been designed specifically to probe the relationship between the conformation of the aminoethyl side chain and the aromatic ring in agonist-receptor interactions. In addition, a strategy is also proposed to develop an agonist ligand that should have high affinity for the 5-HT2A receptor, but which should possess low affinity for the 5-HT2c receptor. A short series of derivatives of a novel template we have recently developed with high affinity for the serotonin 5-HT1A receptor is also proposed and, along with known agonist ligands for this receptor, a homology model for the 5-HT1A receptor will be refined using methods similar to those we used for the 5-HT2A receptor. Finally, we shall continue our investigations into the nature of the biphasic action of the potent hallucinogenic agent LSD, where we have discovered that the effects of LSD in rats are mediated initially by activation of 5-HT2A receptors, but in a later temporal phase dopamine systems appear to be activated. In addition, we shall study the underlying basis for the behavioral sensitization that occurs following long-term LSD administration to rats. These studies will involve examination of a number of antipsychotic drugs to determine whether they can attenuate or block LSD-induced behavioral sensitization in rats either acutely, or following continuous administration. We also propose the synthesis of a 13-hydroxyergoline as a potential dopaminergic compound, to assess the potential dopaminergic activity of the 13-hydroxy metabolite of LSD. These studies may lead to a rat model of schizophrenia that could be very useful in developing and understanding new types of antipsychotic agents.

描述（由申请人提供）：这是一项高度跨学科的建议，旨在继续我们努力了解致幻剂的结构活性关系：在5-羟色胺5-HT2A受体中是激动剂的药物。它涉及计算机辅助的配体设计和受体对接研究，体外和体内药理学以及分子生物学方法。更具体地说，它建立在我们在实验室中开发的5-羟色胺5-HT2A受体的同源模型上，并提出了假定的配体结合域内的许多特定突变。这些突变将与对要合成或已经在我们广泛的文库中合成或已经在我们广泛的文库中的小动物配体的药理学评估结合使用，以检查结合和激活的功能互补，这是目前可用于识别受体内直接配体接触的最强大技术。构象约束的苯乙胺配体也已专门设计，以探测氨基乙基侧链的构象与动力学受体相互作用中的芳环之间的关系。此外，还提出了一种策略来开发应对5-HT2A受体具有高亲和力的激动剂配体，但对5-HT2C受体的亲和力低。还提出了我们最近开发具有高亲和力对5-羟色胺5-HT1A受体的高亲和力的短系列衍生物，还提出了该受体的已知激动剂配体，将使用与我们使用的5-HT2A受体相似的方法来改进5-HT1A受体的同源模型。最后，我们将继续研究有效的致幻剂LSD的双相作用的性质，在那里我们发现，LSD在大鼠中的作用最初是通过5-HT2A受体激活来介导的，但是在随后的颞相多巴胺系统中，大鼠的作用似乎被激活。此外，我们将研究长期对大鼠的LSD给药后发生的行为敏化的基础。这些研究将涉及检查多种抗精神病药，以确定它们是否可以减弱或阻止LSD诱导的大鼠急性或连续给药后的行为敏化。我们还提出将13-羟基羟基酚作为潜在多巴胺能化合物的合成，以评估LSD的13-羟基代谢物的潜在多巴胺能活性。这些研究可能导致精神分裂症的大鼠模型，该模型在开发和理解新型抗精神病药物类型方面可能非常有用。