title: Muscarinic acetylcholine receptor X-ray structures: potential implications for drug development.
abstract: Muscarinic acetylcholine receptor antagonists are widely used as bronchodilating drugs in pulmonary medicine. The therapeutic efficacy of these agents depends on the blockade of M3 muscarinic receptors expressed on airway smooth muscle cells. All muscarinic antagonists currently used as bronchodilating agents show high affinity for all five muscarinic receptor subtypes, thus increasing the likelihood of unwanted side effects. Recent X-ray crystallographic studies have provided detailed structural information about the nature of the orthosteric muscarinic binding site (the conventional acetylcholine binding site) and an 'outer' receptor cavity that can bind allosteric (non-orthosteric) drugs. These new findings should guide the development of selective M3 receptor blockers that have little or no effect on other muscarinic receptor subtypes.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: akruse@stanford.edu.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Kruse
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kobilka
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA. Electronic address: jurgenw@helix.nih.gov.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
mesh_terms: D000818:Animals; D018678:Cholinergic Agents / Q000494:pharmacology; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D006801:Humans; D043585:Receptor, Muscarinic M2 / Q000737:chemistry* / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000737:chemistry* / Q000378:metabolism; D012602:Scopolamine Derivatives / Q000494:pharmacology; D000069447:Tiotropium Bromide
chemical_list: D018678:Cholinergic Agents; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D012602:Scopolamine Derivatives; D000069447:Tiotropium Bromide