Roth Bryan L, Baner Karen, Westkaemper Richard, Siebert Daniel, Rice Kenner C, Steinberg SeAnna, Ernsberger Paul, Rothman Richard B
National Institute of Mental Health Psychoactive Drug Screening Program and Department of Biochemistry, Case Western Reserve University Medical School, Cleveland, OH 44106, USA.
Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11934-9. doi: 10.1073/pnas.182234399. Epub 2002 Aug 21.
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 (3)H-bremazocine binding to cloned kappa opioid receptors. Salvinorin A had no significant activity against a battery of 50 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-HT(2A) 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.
鼠尾草（Salvia divinorum），其主要活性成分是新克罗烷二萜类化合物鼠尾草酸（Salvinorin A），是薄荷科中的一种致幻植物，墨西哥瓦哈卡州的马萨特克人因其精神活性特性而将其用于传统的精神修行中。最近，鼠尾草提取物和鼠尾草酸在美国作为合法致幻剂的使用变得更加广泛。我们发现鼠尾草酸能有效且选择性地抑制（3）H-布马佐辛与克隆的κ阿片受体结合。鼠尾草酸对一系列50种受体、转运体和离子通道均无显著活性，与原型致幻剂麦角酸二乙酰胺相比呈现出独特的特征。功能研究表明，鼠尾草酸在人胚肾-293细胞中表达的克隆κ阿片受体以及豚鼠脑内表达的天然κ阿片受体上是一种强效的κ阿片激动剂。重要的是，鼠尾草酸对5-HT（2A）5-羟色胺受体没有作用，而该受体是经典致幻剂作用的主要分子靶点。据我们所知，鼠尾草酸是第一种天然存在的非含氮阿片受体亚型选择性激动剂。由于鼠尾草酸是一种对κ阿片受体有选择性的拟精神病药物，κ阿片选择性拮抗剂可能代表用于治疗以感知扭曲为特征的疾病（如精神分裂症、痴呆和双相情感障碍）的新型心理治疗化合物。此外，这些结果表明κ阿片受体在人类感知的调节中起重要作用。
