期刊论文详细信息
NEUROPHARMACOLOGY 卷:172
Pharmacological and biotransformation studies of 1-acyl-substituted derivatives of D-lysergic acid diethylamide (LSD)
Article
Halberstadt, Adam L.1,2  Chatha, Muhammad1  Klein, Adam K.1  McCorvy, John D.3  Meyer, Markus R.4  Wagmann, Lea4  Stratford, Alexander5  Brandt, Simon D.6 
[1] Univ Calif San Diego, Dept Psychiat, 9500 Gilman Dr, La Jolla, CA 92093 USA
[2] VA San Diego Healthcare Syst, Res Serv, 3350 La Jolla Village Dr, San Diego, CA 92161 USA
[3] Med Coll Wisconsin, Dept Cell Biol Neurobiol & Anat, Milwaukee, WI 53226 USA
[4] Saarland Univ, Ctr Mol Signaling PZMS, Inst Expt & Clin Pharmacol & Toxicol, Dept Expt & Clin Toxicol, D-66421 Homburg, Germany
[5] Synex Synthet BV, Karveelweg 20, NL-6222 NH Maastricht, Netherlands
[6] Liverpool John Moores Univ, Sch Pharm & Biomol Sci, Byrom St, Liverpool L3 3AF, Merseyside, England
关键词: New psychoactive substances;    LSD;    5-HT2A receptor;    Lysergamides;    Psychedelics;   
DOI  :  10.1016/j.neuropharm.2019.107856
来源: Elsevier
PDF
【 摘 要 】

The ergoline D-lysergic acid diethylamide (LSD) is one of the most potent psychedelic drugs. 1-Acetyl-LSD (ALD-52), a derivative of LSD containing an acetyl group on the indole nitrogen, also produces psychedelic effects in humans and has about the same potency as LSD. Recently, several other 1-acyl-substitued LSD derivatives, including 1-propanoyl-LSD (1P-LSD) and 1-butanoyl-LSD (1B-LSD), have appeared as designer drugs. Although these compounds are assumed to act as prodrugs for LSD, studies have not specifically tested this prediction. The present investigation was conducted to address the gap of information about the pharmacological effects and mechanism-of-action of 1-acyl-substituted LSD derivatives. Competitive binding studies and calcium mobilization assays were performed to assess the interaction of ALD-52, 1P-LSD, and 1B-LSD with serotonin 5-HT2 receptor subtypes. A receptorome screening was performed with 1B-LSD to assess its binding to other potential targets. Head twitch response (HTR) studies were performed in C57BL/6J mice to assess in vivo activation of 5-HT2A (the receptor thought to be primarily responsible for hallucinogenesis). Finally, liquid chromatography/ion-trap mass spectrometry (LC/MS) was used to quantify plasma levels of LSD in Sprague-Dawley rats treated with ALD-52 and 1P-LSD. 1-Acyl-substitution reduced the affinity of LSD for most monoamine receptors, including 5-HT2A sites, by one to two orders of magnitude. Although LSD acts as an agonist at 5-HT2 subtypes, ALD-52, 1P-LSD and 1B-LSD have weak efficacy or act as antagonists in Ca2+-mobilization assays. Despite the detrimental effect of 1-acyl substitution on 5-HT2A affinity and efficacy, 1-acyl-substitued LSD derivatives induce head twitches in mice with relatively high potency. High levels of LSD were detected in the plasma of rats after subcutaneous administration of ALD-52 and 1P-LSD, demonstrating these compounds are rapidly and efficiently deacylated in vivo. These findings are consistent with the prediction that ALD-52, 1P-LSD and 1B-LSD serve as prodrugs for LSD. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.

【 授权许可】

Free   

【 预 览 】
附件列表
Files Size Format View
10_1016_j_neuropharm_2019_107856.pdf 1887KB PDF download
  文献评价指标  
  下载次数:1次 浏览次数:0次