title: Probing the size of a hydrophobic binding pocket within the allosteric site of muscarinic acetylcholine M2-receptors.
abstract: Hexane-bisammonium-type compounds containing lateral phthalimide moieties are known to have a rather high affinity for the allosteric site of muscarinic M2 receptors. In order to get more insight into the contribution of the lateral substituents for alloster binding affinity, a series of compounds with unilaterally varying imide substituents were synthesized and tested for their ability to retard allosterically the dissociation of [3H]N-methylscopolamine from the receptor protein (control t1/2 = 2 min; 3 mM MgHCO4, 50 mM Tris, pH 7.3, 37 degrees C). Among the test compounds, the naphthalimide containing agent (half maximum effect at ECs5,diss = 60 nM) revealed the highest potency. Apparently, its affinity for the allosteric site in NMS-occupied receptors is 20fold higher compared with the phthalimide containing parent compound W 84. Analysis of quantitative structure-activity relationships yielded a parabolic correlation between the volume of the lateral substituents and the allosteric potency. The maximal volume was determined to be approximately 600 A3 suggesting that the allosteric binding site contains a binding pocket of a defined size for the imide moiety.
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Bender
authors.forename: M
authors.initials: M
authors.lastname: Staudt
authors.forename: C
authors.initials: C
authors.lastname: Tränkle
authors.forename: K
authors.initials: K
authors.lastname: Mohr
authors.forename: U
authors.initials: U
authors.lastname: Holzgrabe
mesh_terms: D000818:Animals; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry; D009206:Myocardium / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000737:chemistry* / Q000187:drug effects / Q000648:ultrastructure; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D018727:Muscarinic Antagonists; D000644:Quaternary Ammonium Compounds; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic