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Analytical profile, in vitro metabolism and behavioral properties of the lysergamide 1P-AL-LAD

Brandt, SD, Kavanagh, PV, Westphal, F, Pulver, B, Schwelm, HM, Whitelock, KM, Stratford, A, Auwärter, V and Halberstadt, AL Analytical profile, in vitro metabolism and behavioral properties of the lysergamide 1P-AL-LAD. Drug Testing and Analysis. ISSN 1942-7603 (Accepted)

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Abstract

Lysergic acid diethylamide (LSD) is known to induce powerful psychoactive effects in humans, which cemented its status as an important tool for clinical research. A range of analogues and derivatives has been investigated over the years, including those classified as new psychoactive substances. This study presents the characterization of the novel lysergamide N,N-diethyl-1-propanoyl-6-(prop-2-en-1-yl)-9,10-didehydroergoline-8β-carboxamide (1P-AL-LAD) using various mass spectrometric, gas- and liquid chromatographic and spectroscopic methods. In vitro metabolism studies using pooled human liver microsomes (pHLM) confirmed that 1P-AL-LAD converted to AL-LAD as the most abundant metabolite consistent with the hypothesis that 1P-AL-LAD may act as a prodrug. Fourteen metabolites were detected in total; metabolic reactions included hydroxylation of the core lysergamide ring structure or the N6-allyl group, formation of dihydrodiol metabolites, N-dealkylation, N1-deacylation, dehydrogenation, and combinations thereof. The in vivo behavioral activity of 1P-AL-LAD was evaluated using the mouse head twitch response (HTR), a 5-HT2A-mediated head movement that serves as a behavioral proxy in rodents for human hallucinogenic effects. 1P-AL-LAD induced a dose-dependent increase in HTR counts with an inverted U-shaped dose-response function, similar to lysergic acid diethylamide (LSD), psilocybin, and other psychedelics. Following intraperitoneal injection, the median effective dose (ED50) for 1P-AL-LAD was 491 nmol/kg, making it almost three times less potent than AL-LAD (174.9 nmol/kg). Previous studies have shown that N1-substitution disrupts the ability of lysergamides to activate the 5-HT2A receptor; based on the in vitro metabolism data, 1P-AL-LAD may induce the HTR because it acts as a prodrug and is metabolized to AL-LAD after administration to mice.

Item Type: Article
Uncontrolled Keywords: 0301 Analytical Chemistry; 0601 Biochemistry and Cell Biology; 1115 Pharmacology and Pharmaceutical Sciences; Analytical Chemistry
Subjects: Q Science > QD Chemistry
Q Science > QH Natural history > QH301 Biology
R Medicine > RM Therapeutics. Pharmacology
Divisions: Pharmacy & Biomolecular Sciences
Publisher: Wiley
SWORD Depositor: A Symplectic
Date Deposited: 06 May 2022 09:16
Last Modified: 20 May 2022 12:15
DOI or Identification number: 10.1002/dta.3281
URI: https://researchonline.ljmu.ac.uk/id/eprint/16766

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