title: Characteristics of the ligand-binding site interaction for a series of arecoline-derived muscarinic agonists: a quantum chemical study.
abstract: This work focuses on electronic and conformational structure of bicyclic analogues of arecoline and sulfoarecoline--muscarinic receptor agonists structurally related to 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THPO) and its S-methylsulfonium derivative (DHTO). Conformational freedom of six-member rings containing sulphur and nitrogen has been investigated by means of semiempirical AM1 method. Interaction between 'cationic heads' of two representative compounds and HCO2- ion serving as a model of carboxyl group of Asp in the muscarinic receptor has been modelled using DFT method in local approximation (LDA with VWN exchange correlation functional). Electrostatic potential (ESP) around studied complexes and ligands with added electron (simulation of complex formation) are presented and analysed. Position and depth of ESP minima in a series of studied ligands correlate well with their activity as muscarinic agonists. On the basis of our results the mechanism of ligand-binding site interaction may be elucidated. The calculations allow also for the comparison of bicyclic analogues of arecoline with already existing model for muscarinic pharmacophore and for rationalization of model parameters.
authors.affiliation: Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Cracow. broclawi@trurl.ch.uj.edu.pl
authors.forename: E
authors.initials: E
authors.lastname: Broclawik
authors.forename: T
authors.initials: T
authors.lastname: Borowski
mesh_terms: D001115:Arecoline / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D004563:Electrochemistry; D004578:Electron Spin Resonance Spectroscopy; D004583:Electrons; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008968:Molecular Conformation; D018721:Muscarinic Agonists / Q000737:chemistry* / Q000494:pharmacology*; D011789:Quantum Theory; D011976:Receptors, Muscarinic / Q000737:chemistry* / Q000187:drug effects*
chemical_list: D001643:Bridged Bicyclo Compounds; D007555:Isoxazoles; D008024:Ligands; D018721:Muscarinic Agonists; D011976:Receptors, Muscarinic; D001115:Arecoline; C026804:4,5,6,7-tetrahydroisoxazolo(4,5-c)pyridin-3-ol