LIGANDS FOR OPIOID RECEPTOR SUBTYPES

阿片受体亚型的配体

基本信息

批准号：
3213366
负责人：
Wendel L. Nelson
金额：
$ 13.27万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-07-01 至 1995-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3213366
关键词：
affinity labeling chemical structure function drug design /synthesis /production drug screening /evaluation epoxides guinea pigs inhibitor /antagonist isothiocyanates naltrexone neuropeptide receptor opiate alkaloid opioid receptor receptor binding stimulant /agonist

项目摘要

The long-term objective of this project is to develop electrophilic and photoaffinity ligands for opioid receptors which may be useful in the characterization and/or purification of these receptors. In addition, the compounds may provide long-acting agonists or antagonists. Electrophilic and photoactivatable groups are attached to ligands known to be bound to mu-, kappa-, or delta-opioid receptor subtypes. The compounds would be employed principally as pharmacological tools to aid in characterization of receptor subtypes. The compounds to be prepared are: 1. mu-Antagonists and agonists derived primarily from naltrexone, and less from oxymorphone, in which the electrophilic groups and photoaffinity probes are attached to the 6-, 7-, 8-positions. The major focus of this application is on mu-opioid receptor ligands. 2. Possible electrophilic and photoaffinity probes derived from the selective delta-antagonist naltrindole. 3. Possible electrophilic and photoaffinity probes of selective kappa- antagonist norbinaltorphimine and kappa-agonist ICI-199441. All compounds will be tested in opioid receptor binding assays for selectivity at mu-, kappa-, and delta-subclasses of opioid receptors. Active compounds with high affinity will also be tested for possible irreversible effects. Electrophiles will be preincubated and possible photoaffinity probes will be also be photolyzed. The binding assay will be repeated to determine is there is irreversible binding. Compounds with interesting activities will also be submitted to CPDD for testing in vivo.

该项目的长期目标是发展亲电和阿片类药物受体的光附件配体可能在这些受体的表征和/或纯化。另外，化合物可以提供长效激动剂或拮抗剂。亲电可光活化组附在已知与 Mu-，kappa-或Delta-阿片受体亚型。化合物将是主要用作药理工具，以帮助表征受体亚型。要准备的化合物是： 1。Mu-Antagonists和激动剂主要源自Naltrexone，更少来自矛盾的矛盾，其中亲电的组和光性探针附着在6-，7-，8位。主要重点应用在MU-阿片受体配体上。 2。可能衍生出的亲电和光性探针选择性三角洲 - 抗那ton子。 3。选择性kappa-可能的亲电和光附属探针拮抗剂Norbinaltorphimine和Kappa-Aganist ICI-199441。所有化合物将在阿片类受体结合测定中进行测试阿片受体的Mu-，Kappa-和Delta-囊泡的选择性。还将测试具有高亲和力的活性化合物不可逆转的效果。电力物将被预孵育并可能光性探针也将被光解。装订测定将是重复确定是否存在不可逆的结合。具有有趣的活动还将提交给CPDD进行体内测试。