Design of Small Non-Peptidic Ligands That Alter Heteromerization between Cannabinoid CB1 and Serotonin 5HT2A Receptors

Activation of cannabinoid CB₁ receptors (CB₁R) by agonists induces analgesia but also induces cognitive impairment through the heteromer formed between CB₁R and the serotonin 5HT_2A receptor (5HT_2AR). This side effect poses a serious drawback in the therapeutic use of cannabis for pain alleviation. Peptides designed from the transmembrane helices of CB₁R, which are predicted to bind 5HT_2AR and alter the stability of the CB₁R-5HT_2AR heteromer, have been shown to avert CB₁R agonist-induced cognitive impairment while preserving analgesia. Using these peptides as templates, we have now designed nonpeptidic small molecules that prevent CB₁R-5HT_2AR heteromerization in bimolecular fluorescence complementation assays and the heteromerization-dependent allosteric modulations in cell signaling experiments. These results provide proof-of-principle for the design of optimized ligand-based disruptors of the CB₁R-5HT_2AR heteromer, opening new perspectives for in vivo studies.