STEREOCHEMICAL ASPECTS OF HALLUCINOGENESIS

致幻剂的立体化学方面

基本信息

批准号：
6174590
负责人：
DAVID E NICHOLS
金额：
$ 28.59万
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 2003-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6174590
关键词：
analog chemical structure function chemical substitution dopamine receptor drug design /synthesis /production drug metabolism ergolines laboratory rat lysergic acid diethylamide neuropharmacology oxygen phenylethylamines psychopharmacology receptor binding serotonin receptor stereochemistry stereoisomer tryptamines

项目摘要

DESCRIPTION (from applicant's abstract): The major aims of this proposal are all focused on the serotonin 5-HT2A receptor, which is now being seen as a critical site for normal cognitive function and as a target for a typical antipsychotic agents. In the first aim, the PI will study how the oxygen substitution patterns in phenethylamine type 5-HT2A agonists affect orientation of the oxygen atom unshared electrons, which are clearly determinants of ligand recognition and activation. This information is critical to developing a 3D pharmacophore that can encompass all of the phenethylamine agonists possessing different substitution patterns. This aim will be accomplished by the synthesis of a variety of rigid analogues wherein the oxygen function is tethered into a ring of varying size, that forces the oxygen atom to adopt a particular conformation. Target molecules will be evaluated for both affinity and efficacy at the cloned rat 5-HT2a receptor, and will also be assessed for specificity at the cloned human 5-HT2A, 5-HT2B and 5-HT2C receptors through a collaborative effort. The second aim is directed toward a study of the hypothesis that the late phases of LSD intoxication may resemble certain aspects of paranoid psychosis, a suggestion made by D.X. Freedman. In particular, we hypothesize that the initial 5-HT2A stimulatory effect of LSD sensitizes brain dopamine pathways to the effect of a potent dopaminergic metabolite, 13-hydroxy-LSD, which may accumulate during the action of LSD, and that this metabolite plays a key role in the psychopharmacology of the second temporal phase of LSD intoxication. These studies would have relevance to understanding possible roles of the 5-HT2A receptor in psychosis and schizophrenia. Major effort in this aim will be directed toward the synthesis and characterization of 13-hydroxy ergolines, using new approaches for construction of the ergoline nucleus. Drug discrimination studies will be employed to examine the nature of the LSD cue, as a function of time after administration, with a particular emphasis on the possibility that dopaminergic effects will predominate in the interoceptive cue at later times after LSD administration. The third aim is directed toward the synthesis of new, extremely potent (subnanomolar), agonist ligand for the 5-HT2 family of receptors. The initial target will be a molecule that can be tritiated to provide a radioligand with very high affinity and relatively high specific activity. A fourth aim is directed toward further examination of the effect of ring-fluorination on receptor selectivity of tryptamines. In particular, these studies are directed toward the preparation of new 5-HT1A receptor selective agonists.

描述（来自申请人的摘要）：该提案的主要目的是所有人都专注于5-羟色胺5-HT2A受体，现在被视为正常认知功能的关键部位，作为典型的目标抗精神病药。在第一个目标中，PI将研究氧气如何 5-HT2A激动剂苯胺胺中的替代模式影响方向氧原子未共享电子，它们显然是配体的决定因素识别和激活。此信息对于开发3D至关重要可以涵盖所有具有所有丧偶胺激动剂的药理不同的替代模式。这个目标将通过合成来实现氧气功能被束缚成一个的多种刚性类似物大小的环，迫使氧原子采用特定构象。将评估目标分子的亲和力和功效在克隆的大鼠5-HT2A受体处，还将评估特异性克隆的人类5-HT2A，5-HT2B和5-HT2C受体通过协作努力。第二个目的是针对一个假设的研究 LSD中毒的后期阶段可能类似于偏执的某些方面精神病，D.X。的建议弗里德曼。特别是，我们假设 LSD的最初5-HT2A刺激作用使脑多巴胺敏感达到有效多巴胺能代谢产物，13-羟基-LSD的效果的途径，在LSD的作用过程中可能会累积，并且该代谢产物发挥 LSD第二时间阶段的心理药理学中的关键作用中毒。这些研究将与理解可能 5-HT2A受体在精神病和精神分裂症中的作用。重大努力这个目标将针对合成和表征 13-羟基嗜酸果石，使用新方法来构建ergoline 核。药物歧视研究将用于检查 LSD提示是管理后时间的函数，强调多巴胺能作用将占主导地位的可能性 LSD给药后的后期互感提示。第三个目标是针对新的，极有效的（亚奈摩尔）的诱导，激动剂 5-HT2受体家族的配体。初始目标将是一个分子可以对此提供具有很高亲和力的放射性物体，并且特异性活动相对较高。第四个目标是针对进一步的检查环氟对受体选择性的影响色素。特别是，这些研究针对制备新的5-HT1A受体选择性激动剂。