Comprehensive evaluation of indazole-based synthetic cannabinoid receptor agonists with aliphatic tail groups

Abstract

Synthetic cannabinoid receptor agonists (SCRAs) are a major health challenge. Indazole-based SCRAs continue to evolve through modification of tail and linked groups, although they have mostly been tested under different conditions by different laboratories and their pharmacokinetic properties have been little studied. We prepared and pharmacologically characterized a library of 57 indazole SCRAs combining varying aliphatic N-alkyl tail groups along with common linked groups (e.g., naphthyl, cumyl, adamantyl, and amino-acid-derived motifs). Compounds were profiled for CB1/CB2 binding affinity, functional activity in calcium mobilization assays, and β-arrestin-2 recruitment, followed by human and mouse liver microsomal stability. Extending short aliphatic tails to n-butyl/n-pentyl generally increased CB1 affinity and functional potency, while linkedgroups contributed toward subtype selectivity and signaling, yielding multiple high-efficacy agonists at both receptors. Microsomal studies revealed species differences, with substantially faster clearance in mice than humans for many analogs. Selected potent compounds were advanced to mouse pharmacokinetic studies. Many compounds demonstrated rapid systemic exposure and brain penetrance. Together, these results define structure-activity relationships for indazole SCRAs and support prioritization of emerging analogs with high CB1 efficacy and favorable CNS exposure for further characterization in vivo.