5-HT2A receptor agonism by tert-leucinamide and valinamide synthetic cannabinoids: In vitro and in vivo evidence

Background and purpose: New synthetic cannabinoid receptor agonists (SCRAs) are associated with severe adverse effects, including unexpected psychiatric symptoms. These compounds are mainly active through their potent agonism on the cannabinoid receptors CB1 and CB2. Recently, evidence of the direct interaction of some SCRAs with the serotonergic 5-HT receptors has emerged. Experimental approach: SCRAs were screened for in vitro 5-HT2A receptor activity using AequoScreen® intracellular Ca2+ release and inositol monophosphate (IP1) formation assays. The pharmaco-toxicological effects induced by the administration of the most effective compound in vitro (AB-5'F-BUTINACA) were investigated in male CD-1 mice with specific focus on its interaction with CB1 and 5-HT2A receptors. Key results: Many SCRAs with a valinamide (AB) or tert-leucinamide (ADB) head moiety had in vitro activity at the 5-HT2A receptor at high concentrations with AB-5'F-BUTINACA and ADB-BUTINACA amongst the most efficacious. In vivo studies showed that AB-5'F-BUTINACA caused neurological changes, sensorimotor alteration, antinociception, hypothermia, reduction in breath rate and hypolocomotion in mice. The neurological, sensorimotor, and thermal antinociceptive effects were mediated by CB1 and 5-HT2A receptors, as they were prevented by pretreatment with the selective CB1 and 5-HT2A receptor antagonists (NESS0327 and MDL100907, respectively). Conclusion and implications: This study demonstrated for the first time that SCRAs with a valinamide or tert-leucinamide head moiety activate the 5-HT2A receptor. Agonism of the compound AB-5'F-BUTINACA at the 5-HT2A receptors resulted in in vivo effects. Our data revealed potential risks related to SCRA consumption that could exacerbate unexpected psychiatric conditions.

Background and Purpose New synthetic cannabinoid receptor agonists (SCRAs) are associated with severe adverse effects, including unexpected psychiatric symptoms. These compounds are mainly active through their potent agonism on the cannabinoid receptors CB1 and CB2. Recently, evidence of the direct interaction of some SCRAs with the serotonergic 5-HT receptors has emerged.Experimental Approach SCRAs were screened for in vitro 5-HT2A receptor activity using AequoScreen (R) intracellular Ca2+ release and inositol monophosphate (IP1) formation assays. The pharmaco-toxicological effects induced by the administration of the most effective compound in vitro (AB-5 ' F-BUTINACA) were investigated in male CD-1 mice with specific focus on its interaction with CB1 and 5-HT2A receptors.Key Results Many SCRAs with a valinamide (AB) or tert-leucinamide (ADB) head moiety had in vitro activity at the 5-HT2A receptor at high concentrations with AB-5 ' F-BUTINACA and ADB-BUTINACA amongst the most efficacious. In vivo studies showed that AB-5 ' F-BUTINACA caused neurological changes, sensorimotor alteration, antinociception, hypothermia, reduction in breath rate and hypolocomotion in mice. The neurological, sensorimotor, and thermal antinociceptive effects were mediated by CB1 and 5-HT2A receptors, as they were prevented by pretreatment with the selective CB1 and 5-HT2A receptor antagonists (NESS0327 and MDL100907, respectively).Conclusion and Implications This study demonstrated for the first time that SCRAs with a valinamide or tert-leucinamide head moiety activate the 5-HT2A receptor. Agonism of the compound AB-5 ' F-BUTINACA at the 5-HT2A receptors resulted in in vivo effects. Our data revealed potential risks related to SCRA consumption that could exacerbate unexpected psychiatric conditions.