Medicinal Chemistry and Therapeutic Potential of Muscarinic M3 Antagonists Ilaria Peretto, 1 Paola Petrillo, 1 and Bruno P. Imbimbo 2 1 NiKem Research, Via Zambeletti 25, 20021 Baranzate, Milan, Italy 2 Research and Development, Chiesi Farmaceutici S.p.A., Via Palermo 26/A, 43100 Parma, Italy Published online 27 April 2009 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/med.20158 . Abstract: Muscarinic acetylcholine receptors belong to the G-protein-coupled receptors family. Currently five different receptor subtypes have been identified and cloned. M3 receptor subtypes are coupled to G q family proteins and increase phosphatidyl inositol hydrolysis and calcium release from internal stores. They are widely distributed both in the central nervous system and in the periphery. At the central level, M3 receptor subtypes are involved in modulation of neurotransmitter release, temperature homeostasis, and food intake, while in the periphery they induce smooth muscle contraction, gland secretion, indirect relaxation of vascular smooth muscle, and miosis. The main therapeutic applications of M3 antagonists include overactive bladder (OAB), chronic obstructive pulmonary disease (COPD), and pain-predominant irritable bowel syndrome (IBS). The introduction of selective M3 antagonists has not improved clinical efficacy compared with the old non-selective antimuscarinics but has reduced the rate of adverse events mediated by the blockade of cardiac M2 receptors (tachycardia) and central M1 receptors (cognitive impairment). Improved tolerability has been obtained also with controlled release or with inhaled formulations. However, there is still a need for safer M3 antagonists for the treatment of COPD and better-tolerated and more effective compounds for the therapy of OAB. New selective muscarinic M3 antagonists currently in early discovery and under development have been designed to address these issues. However, as M3 receptors are widely located in various tissues including salivary glands, gut smooth muscles, iris, and ciliary muscles, further clinical improvements may derive from the discovery and the development of new compounds with tissue rather than muscarinic receptor subtype selectivity. & 2009 Wiley Periodicals, Inc. Med Res Rev, 29, No. 6, 867–902, 2009 Key words: muscarinic antagonist; M3 antagonist; anticholinergic; muscarinic pharmacology; antimuscarinics in clinic 1. INTRODUCTION Muscarinic acetylcholine (ACh) receptors are members of the G-protein-coupled receptor family. They are activated by ACh and muscarine and blocked by atropine. Presently, five Correspondence to: Ilaria Peretto, NiKem Research, Via Zambeletti 25, 20021 Baranzate, Milan, Italy, E-mail: Ilaria.Peretto@ nikemresearch.com Medicinal Research Reviews, Vol. 29, No. 6, 867--902, 2009 & 2009 Wiley Periodicals, Inc.