Exploring stereochemical and conformational requirements at cannabinoid receptors for synthetic cannabinoids related to SDB-006, 5F-SDB-006, CUMYL-PICA, and 5F-CUMYL-PICA

Adam Ametovski, Christa Macdonald, Jamie J. Manning, S. A. Syed Haneef, Marina Santiago, Lewis Martin, Eric Sparkes, Andrew Reckers, Roy R. Gerona, Mark Connor, Michelle Glass, Samuel D. Banister*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Synthetic cannabinoid receptor agonists (SCRAs) represent the most rapidly expanding class of new psychoactive substances (NPSs). Despite the prevalence and potency of recent chiral indole-3-carboxamide SCRAs, few pharmacological data are available regarding the enantiomeric bias of these NPSs toward human CB1 and CB2 receptors. A series of homochiral indole-3-carboxamides derived from (S)- and (R)-α-methylbenzylamine and featuring variation of the 1-alkyl substituent were prepared, pharmacologically evaluated, and compared to related achiral congeners derived from cumyl- and benzylamine. Competitive binding assays demonstrated that all analogues derived from either enantiomer of α-methylbenzylamine (14-17) showed affinities for CB1 (Ki = 47.9-813 nM) and CB2 (Ki = 47.9-347 nM) that were intermediate to that of the corresponding benzylic (10-13, CB1 Ki = 550 nM to >10 μM; CB2 Ki = 61.7 nM to >10 μM) and cumyl derivatives (6-9, CB1 Ki = 12.6-21.4 nM; CB2 Ki = 2.95-24.5 nM). In a fluorometric membrane potential assay, all α-methylbenzyl analogues (excluding 17) were potent, efficacious agonists of CB1 (EC50 = 32-464 nM; Emax = 89-104%) and low efficacy agonists of CB2 (EC50 = 54-500 nM; Emax = 52-77%), with comparable or greater potency than the benzyl analogues and much lower potency than the cumyl derivatives, consistent with binding trends. The relatively greater affinity and potency of (S)-14-17 compared to (R)-14-17 analogues at CB1 highlighted an enantiomeric bias for this series of SCRAs. Molecular dynamics simulations provided a conformational basis for the observed differences in agonist potency at CB1 pending benzylic substitution.

Original languageEnglish
Pages (from-to)3672-3682
Number of pages11
JournalACS Chemical Neuroscience
Volume11
Issue number21
DOIs
Publication statusPublished - 4 Nov 2020

Keywords

  • Cannabinoid
  • pharmacology
  • CUMYL
  • PICA
  • CHMICA
  • FUBICA

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