title: Muscarinic allosteric enhancers of ligand binding: pivotal pharmacophoric elements in hexamethonio-type agents.
abstract: Bisphthalimidopropyl-substituted hexamethonio compounds have been established as allosteric modulators of ligand binding to muscarinic acetylcholine receptors. Enhancers of ligand binding are of special interest. This study aimed to unravel the structural elements inducing positive cooperativity with the binding of an antagonist. [(3)H]-N-methylscopolamine binding to muscarinic M(2) receptors was measured in porcine heart homogenates. Dimethylation, but not monomethylation, of the lateral propyl chain in combination with an affinity increasing aromatic imide moiety, such as a 5-methylphthalimide and naphthalimide, on the same side of the molecule shifts the cooperativity toward positive values, resulting in enhancers of antagonist binding. Thus, lateral side chain dimethylation is a pivotal pharmacophoric element for positive cooperativity in hexamethonio-type muscarinic allosteric agents.
authors.affiliation: Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Muth
authors.forename: Matthias
authors.initials: M
authors.lastname: Sennwitz
authors.forename: Klaus
authors.initials: K
authors.lastname: Mohr
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D018678:Cholinergic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018738:Hexamethonium / Q000737:chemistry*; D066298:In Vitro Techniques; D008024:Ligands; D008745:Methylation; D018727:Muscarinic Antagonists / Q000378:metabolism / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D019832:N-Methylscopolamine / Q000378:metabolism / Q000494:pharmacology; D010797:Phthalimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D018678:Cholinergic Agents; D008024:Ligands; D018727:Muscarinic Antagonists; D010797:Phthalimides; D011976:Receptors, Muscarinic; D018738:Hexamethonium; D019832:N-Methylscopolamine