Therapeutic opportunities from muscarinic receptor research

Muscarinic acetylcholine receptor subtypes have been the subjects of research for at least a quarter of a century. Nonetheless, there are few selective muscarinic receptor ligands presently used as therapeutics. The extensive development of muscarinic M(1) receptor agonists for the treatment of cognitive dysfunction has culminated in a series of unsuccessful drug candidates, which reflects a lack of understanding of the disease and the role played by muscarinic cholinergic transmission. Paradoxically, the most successful antagonist approved for use in urinary incontinence is the nonselective muscarinic receptor antagonist tolterodine. This deficit in subtype-selective ligands could be circumvented by the development of transgenic mice, each lacking functional M(1), M(2), M(3), M(4) or M(5) receptors. In this article, the current status of muscarinic receptor research is critically assessed.