Pharmacological and biotransformation studies of 1-acyl-substituted derivatives of d-lysergic acid diethylamide (LSD). Neuropharmacology 2020 Aug 01;172:107856
Date
11/23/2019Pubmed ID
31756337Pubmed Central ID
PMC9191647DOI
10.1016/j.neuropharm.2019.107856Scopus ID
2-s2.0-85076826541 (requires institutional sign-in at Scopus site) 21 CitationsAbstract
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'.
Author List
Halberstadt AL, Chatha M, Klein AK, McCorvy JD, Meyer MR, Wagmann L, Stratford A, Brandt SDAuthor
John McCorvy PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBehavior, Animal
Binding, Competitive
Biotransformation
Calcium Signaling
Drug Evaluation, Preclinical
Hallucinogens
Lysergic Acid Diethylamide
Male
Mice
Mice, Inbred C57BL
Prodrugs
Rats
Rats, Sprague-Dawley
Receptors, Serotonin, 5-HT2
Serotonin 5-HT2 Receptor Agonists
Serotonin 5-HT2 Receptor Antagonists
