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 (K_i = 47.9-813 nM) and CB2 (K_i = 47.9-347 nM) that were intermediate to that of the corresponding benzylic (10-13, CB1 K_i = 550 nM to >10 μM; CB2 K_i = 61.7 nM to >10 μM) and cumyl derivatives (6-9, CB1 K_i = 12.6-21.4 nM; CB2 K_i = 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; E_max = 89-104%) and low efficacy agonists of CB2 (EC₅₀ = 54-500 nM; E_max = 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.

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