5‐HT 2A receptor agonism by tert ‐leucinamide and valinamide synthetic cannabinoids: In vitro and in vivo evidence
Giorgia Corli, Deborah Rudin, Dino Luethi, Matthias E. Liechti, Sabrine Bilel, Matteo Marti, Henrik Gréen, Manuela Carla Monti, Caitlyn Norman
British Journal of Pharmacology May 5, 2026 DOI: 10.1111/bph.70457 via OpenAlex
Summary
Some new synthetic cannabinoid receptor agonists (SCRAs) also directly activate the serotonin 5-HT₂A receptor, which may contribute to unexpected psychiatric side effects. Many SCRAs with a valinamide or tert-leucinamide head moiety showed in vitro activity at the 5-HT₂A receptor at high concentrations. In mice, the compound AB-5′F-BUTINACA caused neurological changes, sensorimotor alteration, antinociception, hypothermia, reduced breath rate, and hypolocomotion. These effects were mediated by both CB₁ and 5-HT₂A receptors, as they were prevented by selective antagonists. The findings indicate potential risks of SCRA consumption that could exacerbate unexpected psychiatric conditions.
Study at a glance
| Characteristics | Experimental study (in vitro and in vivo) Peer reviewed |
|---|---|
| Population | Male CD-1 mice |
| Topics | Serotonin |
| Keywords | In vivo In vitro Agonism Functional selectivity Cannabinoid receptor agonists |
| Key finding | Synthetic cannabinoid receptor agonists with valinamide or tert-leucinamide head moieties activate the 5-HT₂A receptor, and agonism of AB-5′F-BUTINACA at this receptor produces in vivo effects mediated by both CB₁ and 5-HT₂A receptors. |
Abstract
Abstract 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 CB 1 and CB 2 . 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‐HT 2A receptor activity using AequoScreen® intracellular Ca 2+ release and inositol monophosphate (IP 1 ) 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 CB 1 and 5‐HT 2A receptors. Key Results Many SCRAs with a valinamide (AB) or tert ‐leucinamide (ADB) head moiety had in vitro activity at the 5‐HT 2A 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 CB 1 and 5‐HT 2A receptors, as they were prevented by pretreatment with the selective CB 1 and 5‐HT 2A 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‐HT 2A receptor. Agonism of the compound AB‐5′F‐BUTINACA at the 5‐HT 2A receptors resulted in in vivo effects. Our data revealed potential risks related to SCRA consumption that could exacerbate unexpected psychiatric conditions.