The polypharmacological profiles of xanomeline and N-desmethylxanomeline

The muscarinic agonist xanomeline, in combination with the peripherally restricted muscarinic antagonist trospium, has recently been approved for treatment of schizophrenia. Xanomeline represents the first approved antipsychotic drug without apparent activity at D₂-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.

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.

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.

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.