Glatfelter Grant C, Pottie Eline, Partilla John S, Sherwood Alexander M, Kaylo Kristi, Pham Duyen N K, Naeem Marilyn, Sammeta Vamshikrishna Reddy, DeBoer Stacie, Golen James A, Hulley Elliott B, Stove Christophe P, Chadeayne Andrew R, Manke David R, Baumann Michael H
Designer Drug Research Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland 21224, United States.
Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Campus Heymans, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
ACS Pharmacol Transl Sci. 2022 Nov 2;5(11):1181-1196. doi: 10.1021/acsptsci.2c00177. eCollection 2022 Nov 11.
4-Phosphoryloxy-,-dimethyltryptamine (psilocybin) is a naturally occurring tertiary amine found in many mushroom species. Psilocybin is a prodrug for 4-hydroxy-,-dimethyltryptamine (psilocin), which induces psychedelic effects via agonist activity at the serotonin (5-HT) 2A receptor (5-HT). Several other 4-position ring-substituted tryptamines are present in psilocybin-containing mushrooms, including the secondary amine 4-phosphoryloxy--methyltryptamine (baeocystin) and the quaternary ammonium 4-phosphoryloxy-,,-trimethyltryptamine (aeruginascin), but these compounds are not well studied. Here, we investigated the structure-activity relationships for psilocybin, baeocystin, and aeruginascin, as compared to their 4-acetoxy and 4-hydroxy analogues, using and methods. Broad receptor screening using radioligand binding assays in transfected cells revealed that secondary and tertiary tryptamines with either 4-acetoxy or 4-hydroxy substitutions display nanomolar affinity for most human 5-HT receptor subtypes tested, including the 5-HT and the serotonin 1A receptor (5-HT). The same compounds displayed affinity for 5-HT and 5-HT in mouse brain tissue and exhibited agonist efficacy in assays examining 5-HT-mediated calcium mobilization and β-arrestin 2 recruitment. In mouse experiments, only the tertiary amines psilocin, psilocybin, and 4-acetoxy-,-dimethyltryptamine (psilacetin) induced head twitch responses (ED 0.11-0.29 mg/kg) indicative of psychedelic-like activity. Head twitches were blocked by 5-HT antagonist pretreatment, supporting 5-HT involvement. Both secondary and tertiary amines decreased body temperature and locomotor activity at higher doses, the effects of which were blocked by 5-HT antagonist pretreatment. Across all assays, the pharmacological effects of 4-acetoxy and 4-hydroxy compounds were similar, and these compounds were more potent than their 4-phosphoryloxy counterparts. Importantly, psilacetin appears to be a prodrug for psilocin that displays substantial serotonin receptor activities of its own.
4-磷酸氧基-N，N-二甲基色胺（裸盖菇素）是一种天然存在的叔胺，存在于许多蘑菇品种中。裸盖菇素是4-羟基-N，N-二甲基色胺（脱磷酸裸盖菇素）的前体药物，它通过对5-羟色胺（5-HT）2A受体（5-HT2AR）的激动剂活性诱导迷幻效果。含裸盖菇素的蘑菇中还存在其他几种4-位环取代色胺，包括仲胺4-磷酸氧基-N-甲基色胺（巴氏丝盖伞素）和季铵盐4-磷酸氧基-N，N，N-三甲基色胺（铜绿菌素），但这些化合物尚未得到充分研究。在这里，我们使用[具体方法1]和[具体方法2]研究了裸盖菇素、巴氏丝盖伞素和铜绿菌素与其4-乙酰氧基和4-羟基类似物相比的构效关系。在转染细胞中使用放射性配体结合试验进行的广泛受体筛选显示，具有4-乙酰氧基或4-羟基取代的仲胺和叔胺对大多数测试的人类5-HT受体亚型具有纳摩尔亲和力，包括5-HT2AR和5-羟色胺1A受体（5-HT1AR）。相同的化合物在小鼠脑组织中对5-HT2AR和5-HT1AR显示出亲和力，并在检测5-HT介导的钙动员和β-抑制蛋白2募集的试验中表现出激动剂效力。在小鼠实验中，只有叔胺脱磷酸裸盖菇素、裸盖菇素和4-乙酰氧基-N，N-二甲基色胺（裸盖菌素）诱导了表明类似迷幻活性的头部抽搐反应（ED50为0.11-0.29mg/kg）。5-HT拮抗剂预处理可阻断头部抽搐，支持5-HT的参与。仲胺和叔胺在较高剂量下均降低体温和运动活性，5-HT拮抗剂预处理可阻断这些作用。在所有试验中，4-乙酰氧基和4-羟基化合物的药理作用相似，并且这些化合物比其4-磷酸氧基对应物更有效。重要地是，裸盖菌素似乎是脱磷酸裸盖菇素的前体药物，其自身显示出显著的5-羟色胺受体活性。
