In vivo evaluation of synthetic cannabinoid JWH-018 derivatives as potential new psychoactive substances

Abstract

Abstract Synthetic cannabinoid receptor agonists constitute a prominent class of new psychoactive substances (NPS), in which minor structural modifications can markedly influence in vivo pharmacological outcomes. In this study, methoxy-substituted derivatives of JWH-018 were synthesized to examine the effect of substitution position on behavioral activity. JWH-018–5-OMe and JWH-018–6-OMe were evaluated using four in vivo assays, including catalepsy, hypothermia, analgesia, and locomotor activity. JWH-018–5-OMe selectively reduced rectal temperature, with limited effects observed in catalepsy, analgesia, and locomotor activity. Notably, JWH-018–6-OMe elicited robust and dose-dependent effects across all four behavioral endpoints, closely resembling the pharmacological profile of the parent compound, JWH-018 . Collectively, these results demonstrate that structural variations on the indole scaffold can produce measurable psychoactive effects, underscoring the importance of continued evaluation of indole-based synthetic cannabinoids within the NPS framework.