Design of Small\nNon-Peptidic Ligands That Alter Heteromerization\nbetween Cannabinoid CB<sub>1</sub> and Serotonin 5HT<sub>2A</sub> Receptors

Activation of cannabinoid CB<sub>1</sub> receptors (CB<sub>1</sub>R) by agonists induces analgesia but also induces cognitive\nimpairment\nthrough the heteromer formed between CB<sub>1</sub>R and the serotonin\n5HT<sub>2A</sub> receptor (5HT<sub>2A</sub>R). This side effect poses\na serious drawback in the therapeutic use of cannabis for pain alleviation.\nPeptides designed from the transmembrane helices of CB<sub>1</sub>R, which are predicted to bind 5HT<sub>2A</sub>R and alter the stability\nof the CB<sub>1</sub>R-5HT<sub>2A</sub>R heteromer, have been shown\nto avert CB<sub>1</sub>R agonist-induced cognitive impairment while\npreserving analgesia. Using these peptides as templates, we have now\ndesigned nonpeptidic small molecules that prevent CB<sub>1</sub>R-5HT<sub>2A</sub>R heteromerization in bimolecular fluorescence complementation\nassays and the heteromerization-dependent allosteric modulations in\ncell signaling experiments. These results provide proof-of-principle\nfor the design of optimized ligand-based disruptors of the CB<sub>1</sub>R-5HT<sub>2A</sub>R heteromer, opening new perspectives for <i>in vivo</i> studies.