Development of covalent agonists for the muscarinic acetylcholine receptor.

Binding affinity and residence time of endogenous and synthetic receptor ligands are often poor at the tissue to be treated. Covalent ligands targeting G protein-coupled receptors (GPCRs) have gained significant interest because they unite the high specificity and selectivity with the prolonged activity resulting from irreversible or slowly reversible binding. Using the muscarinic acetylcholine receptor (mAChR) agonists iperoxo (5), PR15 (7), and carbachol (9) as lead compounds, we developed the covalent muscarinic receptor agonists 8 and 10 functionalized by a mustard-type reactive group. Radioligand depletion and functional properties clearly indicated covalent binding and activation of the therapeutically relevant muscarinic acetylcholine receptor.