Salvinorin A:: A potent naturally occurring nonnitrogenous κ opioid selective agonist

被引:630
作者
Roth, BL
Baner, K
Westkaemper, R
Siebert, D
Rice, KC
Steinberg, S
Ernsberger, P
Rothman, RB [1 ]
机构
[1] Case Western Reserve Univ, Sch Med, NIMH, Drug Screening Program, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA
[3] Case Western Reserve Univ, Sch Med, Dept Psychiat, Cleveland, OH 44106 USA
[4] Case Western Reserve Univ, Sch Med, Dept Neurosci, Cleveland, OH 44106 USA
[5] Case Western Reserve Univ, Sch Med, Dept Pharmacol & Nutr, Cleveland, OH 44106 USA
[6] NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA
[7] Virginia Commonwealth Univ Med Coll Virginia, Dept Med Chem, Richmond, VA 23298 USA
[8] Salvia Divinorum Res & Informat Ctr, Malibu, CA 90263 USA
[9] NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA
关键词
D O I
10.1073/pnas.182234399
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Salvia divinorum, whose main active ingredient is the neoclerodane diterpene Salvinorin A, is a hallucinogenic plant in the mint family that has been used in traditional spiritual practices for its psychoactive properties by the Mazatecs of Oaxaca, Mexico. More recently, S. divinorum extracts and Salvinorin A have become more widely used in the U.S. as legal hallucinogens. We discovered that Salvinorin A potently and selectively inhibited H-3-bremazocine binding to cloned kappa opioid receptors. Salvinorin A had no significant activity against a battery of SO receptors, transporters, and ion channels and showed a distinctive profile compared with the prototypic hallucinogen lysergic acid diethylamide. Functional studies demonstrated that Salvinorin A is a potent kappa opioid agonist at cloned kappa opioid receptors expressed in human embryonic kidney-293 cells and at native kappa opioid receptors expressed in guinea pig brain. Importantly, Salvinorin A had no actions at the 5-HT2A serotonin receptor, the principal molecular target responsible for the actions of classical hallucinogens. Salvinorin A thus represents, to our knowledge, the first naturally occurring nonnitrogenous opioid-receptor subtype-selective agonist. Because Salvinorin A is a psychotomimetic selective for kappa opioid receptors, kappa opioid-selective antagonists may represent novel psychotherapeutic compounds for diseases manifested by perceptual distortions (e.g., schizophrenia, dementia, and bipolar disorders). Additionally, these results suggest that kappa opioid receptors play a prominent role in the modulation of human perception.
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收藏
页码:11934 / 11939
页数:6
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