Structure-Activity of Opioid Drugs

阿片类药物的结构-活性

基本信息

批准号：
7733854
负责人：
Richard Rothman
金额：
$ 59.76万
依托单位：
NATIONAL INSTITUTE ON DRUG ABUSE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7733854
关键词：
ARRB2 Absence of pain sensation Adverse effects Affinity Agonist Analgesics Antidepressive Agents Area Behavior Behavioral Benzamides Biological Factors Chemicals Cocaine Data Dependence Development Dopamine Endorphins Heroin Human In Vitro Ligands Mediating Modeling Modification Morphine Narcotic Abuses Narcotic Antagonists Narcotics Nucleus Accumbens Opioid Opioid Peptide Opioid Receptor Oxides Pharmaceutical Chemistry Pharmaceutical Preparations Physiological Play Positioning Attribute Prevention Property Publications Purpose Rattus Receptor Down-Regulation Receptor Signaling Regulation Relapse Reporting Research Role Self Administration Series Stress Structure System alcohol effect analog chronic pain delta opioid receptor enantiomer endogenous opioids immune function in vivo kappa opioid receptors mu opioid receptors novel phenylmorphan prevent receptor receptor internalization reinforced behavior salvinorin A tool

ARRB2 Absence of pain sensation Adverse effects Affinity Agonist Analgesics Antidepressive Agents Area Behavior Behavioral Benzamides Biological Factors Chemicals Cocaine Data Dependence Development Dopamine Endorphins Heroin Human In Vitro Ligands Mediating Modeling Modification Morphine Narcotic Abuses Narcotic Antagonists Narcotics Nucleus Accumbens Opioid Opioid Peptide Opioid Receptor Oxides Pharmaceutical Chemistry Pharmaceutical Preparations Physiological Play Positioning Attribute Prevention Property Publications Purpose Rattus Receptor Down-Regulation Receptor Signaling Regulation Relapse Reporting Research Role Self Administration Series Stress Structure System alcohol effect analog chronic pain delta opioid receptor enantiomer endogenous opioids immune function in vivo kappa opioid receptors mu opioid receptors novel phenylmorphan prevent receptor receptor internalization reinforced behavior salvinorin A tool

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项目摘要

Significant progress was made in the last reporting period, resulting in seven publications. We identified a a potent mu-agonist delta-antagonist, and an exceedingly potent antinociceptive in the enantiomeric C9-Substituted 5-(3-Hydroxyphenyl)-N-phenylethylmorphan series. Another study reported the synthesis and pharmacological effects of the enantiomers of the N-phenethyl analogues of the ortho and para e- and f-oxide-bridged phenylmorphans. Further progress was made in the structure-activity of salvinorin A analogs, including exploration of the 1-position. Importantly, we reported herkinorin analogues with differential beta-arrestin-2 interactions. As described in that study: "Salvinorin A is a psychoactive natural product that has been found to be a potent and selective kappa opioid receptor agonist in vitro and in vivo. The activity of salvinorin A is unusual compared to other opioids such as morphine in that it mediates potent kappa opioid receptor signaling yet leads to less receptor down-regulation than observed with other kappa agonists. Our initial chemical modifications of salvinorin A have yielded one analogue, herkinorin ( 1c), with high affinity at the mu-OR. We recently reported that 1c does not promote the recruitment of beta-arrestin-2 to the mu-OR or receptor internalization. Here we describe three new derivatives of 1c ( 3c, 3f, and 3i) with similar properties and one, benzamide 7b, that promotes recruitment of beta-arrestin-2 to the mu-OR and receptor internalization. When the important role mu opioid receptor regulation plays in determining physiological responsiveness to opioid narcotics is considered, mu opioids derived from salvinorin A may offer a unique template for the development of functionally selective mu opioid receptor-ligands with the ability to produce analgesia while limiting adverse side effects.

在最后一个报告期间取得了重大进展，导致七个出版物。我们确定了一个有效的MU-DELTA抗逆抗剂，并且在对映体C9取代的5-（3-羟基苯基）-n-苯基乙基甲基苯丙胺系列中具有极有效的抗伤害感受。另一项研究报道了矫正和para e-和para e- e- e- e-和f-氧化物桥的苯基苯基苯基苯基苯基苯基类似物的对映异构体的合成和药理作用。在类似物的salvinorin a类似物的结构活性中取得了进一步的进步，包括对1位的探索。重要的是，我们报道了具有差异β-arrestin-2相互作用的Herkinorin类似物。如该研究所述：萨氏素蛋白A是一种精神活性的天然产品，在体外和体内被认为是一种有力的选择性Kappa阿片类药物受体激动剂。与其他阿片类药物相比，Salvinorin a的活性与其他阿片类药物相比，与其他kappa aphopio signalliss相比，与其他阿片类药物相比，与其他阿片类药物相比，与其他阿片类药物相比，其他阿片类药物的活性相比是不寻常的。 Salvinorin A的修饰产生了一个类似物，在MU-OR上具有高亲和力，我们最近报告说，1C不会促进beta-arrestin-2的募集到MU-OR或受体内在化的beta-arrestin-2。考虑到MU阿片受体调节在确定对阿片类药物的生理反应性中的重要作用在确定阿片类药物的生理响应中，MU阿片类药物可能会为有效的MU阿片类副作用的开发提供独特的模板，而在确定阿片类药物的生理响应中，beta-arrestin-2的beta-arrestin-2。