Pharmacological and biotransformation studies of 1-acyl-substituted derivatives of -lysergic acid diethylamide (LSD)

Abstract

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 1butanoyl-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-HT 2 performed with 1B-LSD to assess its binding to othe (HTR) studies were performed in C57BL/6J mice to assess in vivo activation of 5-HT 2A (the receptor thought to be primarily responsible for ha chromatography/ion-trap mass spectrometry (LC/MS) was used to quantify plasma levels of LSD in Sprague-Dawley rats treated with ALD-52 and affinity of LSD for most monoamine receptors, inclu 2A sites, by one to two orders of magnitude. Although LSD acts as an agonist at 5-HT 2 subtypes, ALD-52, 1P-LSD and 1B-LSD had weak efficacy or acted as antagonists in Ca 2+-mobilization assays. Despite the detrimental effect of 1-acyl substitution on 5-HT 2A atives 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 ted in vivo. These findings are consistent with the prediction that ALD-52, 1P-LSD and 1B-LSD serve as pro-drugs for LSD. receptor subtypes. A receptorome screening was r potential targets. Head twitch response llucinogenesis). Finally, liquid 1P-LSD. 1-Acyl-substitution reduced the ding 5-HT affinity and efficacy, 1-acyl-substitued LSD deriv these compounds are rapidly and efficiently deacyla

Return of the lysergamides. Part VI: Analytical and behavioural characterization of 1‐cyclopropanoyl‐d‐lysergic acid diethylamide (1CP‐LSD)

“…ALD‐52, 1P‐LSD, and 1B‐LSD have been shown to elicit the HTR and it appears that this is the result of LSD formation in vivo 18,24 . Compared with LSD, ALD‐52, 1P‐LSD, and 1B‐LSD bind to the 5‐HT 2A receptor with lower affinity and act as very weak 5‐HT 2A partial agonists in a Ca 2+ flux assay 24 …”

“…It was shown recently that 1‐acylated lysergamides likely serve as prodrugs to either LSD (1P‐LSD, 1B‐LSD, ALD‐52) 18,19,22–24 or N 6 ‐ethyl‐nor‐LSD (ETH‐LAD) (from 1P‐ETH‐LAD), 19,22 suggesting that the detection of the parent 1‐acylated lysergamide in vivo following ingestion might be challenging.…”

“…Clinical research with newer lysergamides has yet to be carried out in detail but serotonergic hallucinogens such as LSD induce the head‐twitch response (HTR) in mice and rats, which reflects 5‐HT 2A receptor activation (the primary target of hallucinogens in the CNS) 25,26 . In addition to having the ability to differentiate between hallucinogenic and non‐hallucinogenic 5‐HT 2A receptor agonists, 27,28 the HTR assay also allows in vivo potencies to be compared in a manner that has cross‐species translational relevance to humans 24,29 . ALD‐52, 1P‐LSD, and 1B‐LSD have been shown to elicit the HTR and it appears that this is the result of LSD formation in vivo 18,24 .…”

“…In addition to having the ability to differentiate between hallucinogenic and non‐hallucinogenic 5‐HT 2A receptor agonists, 27,28 the HTR assay also allows in vivo potencies to be compared in a manner that has cross‐species translational relevance to humans 24,29 . ALD‐52, 1P‐LSD, and 1B‐LSD have been shown to elicit the HTR and it appears that this is the result of LSD formation in vivo 18,24 . Compared with LSD, ALD‐52, 1P‐LSD, and 1B‐LSD bind to the 5‐HT 2A receptor with lower affinity and act as very weak 5‐HT 2A partial agonists in a Ca 2+ flux assay 24 …”

Prodrugs of New Psychoactive Substances (NPS): A New Challenge

“…Recent investigations have also shown that the affinity of ALD‐52, 1P‐LSD, and 1B‐LSD to most monoamine receptors dropped by one to two orders of magnitude compared to LSD and that they showed a weak efficacy or even acted as antagonists in Ca 2+ ‐ mobilization assays. The fact that these substances however were able to induce the head‐twitch response in mice and that LSD was detected in rat plasma samples was also consistent with the idea that 1‐acyl‐substituted LSD derivatives might serve as prodrugs .…”