The polypharmacological profiles of xanomeline and N‐desmethylxanomeline

BACKGROUND AND PURPOSE: -dopamine receptors. In humans, xanomeline is reported to be metabolised to N-desmethylxanomeline, which has a similar pharmacokinetic profile to xanomeline, although its pharmacology has not been reported. EXPERIMENTAL APPROACH: We profiled xanomeline and N-desmethylxanomeline using radioligand binding assays, PRESTO-Tango screening across the human GPCRome, and orthogonal functional assays (TRUPATH BRET2 G-protein dissociation, BRET1 β-arrestin recruitment, calcium flux and GloSensor cAMP). We summarised signalling with transduction coefficients and clustered these values. KEY RESULTS: We discovered that xanomeline and N-desmethylxanomeline have potent agonist and antagonist actions at many biogenic amine G-protein coupled receptors. These results suggest that at least some of the actions of xanomeline and N-desmethylxanomeline could be mediated by off-target actions at serotonergic, dopaminergic, histaminergic, adrenergic and other receptors. CONCLUSIONS AND IMPLICATIONS: These standardised receptorome-wide data identify candidate secondary targets beyond muscarinic receptors that may contribute to efficacy and/or tolerability, depending on exposure and target engagement. The dataset provides a quantitative framework for prioritising targets for mechanistic follow-up and optimising muscarinic-based therapeutics. We discuss the potential implications of these findings.