title: Molecular modeling of the interaction of diagnostic radiopharmaceuticals with receptor proteins: m2 antagonist binding to the muscarinic m2 subtype receptor.
abstract: Models of the m2 muscarinic receptor have been built and acetylcholine and an antagonist of the quinuclidinyl benzilate family docked to the putative active site. We have incorporated aspects of homology, site-directed mutagenesis studies and structure-activity studies of specific lead compounds in the construction of our receptor models with a primary focus on the structure of the binding sites. We have observed a deep pocket binding of 5-BrQNT, suggesting a plausible explanation for the observation that agonists and antagonists do not bind competitively. The results of these computational studies are interpreted within the context of the observed in vitro results. Our goal is to assist in the development of subtype receptor selective radiopharmaceuticals for use in PET and SPECT.
authors.affiliation: Department of Radiology, University of Chicago, IL 60637, USA.
authors.forename: O H
authors.initials: OH
authors.lastname: Kapp
authors.forename: J
authors.initials: J
authors.lastname: Siemion
authors.forename: W C
authors.initials: WC
authors.lastname: Eckelman
authors.forename: V I
authors.initials: VI
authors.lastname: Cohen
authors.forename: R C
authors.initials: RC
authors.lastname: Reba
mesh_terms: D000109:Acetylcholine / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D003198:Computer Simulation; D006016:Glycolates / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018727:Muscarinic Antagonists / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D011812:Quinuclidines / Q000737:chemistry / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000378:metabolism; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000737:chemistry* / Q000378:metabolism
chemical_list: C110326:5-BrQNT; D006016:Glycolates; D008024:Ligands; D018727:Muscarinic Antagonists; D011812:Quinuclidines; D019275:Radiopharmaceuticals; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D000109:Acetylcholine