title: Probing the pharmacophore for allosteric ligands of muscarinic M2 receptors: SAR and QSAR studies in a series of bisquaternary salts of caracurine V and related ring systems.
abstract: Allosteric effects on muscarinic acetylcholine M(2) receptors were examined in a series of bisquaternary salts of the Strychnos alkaloid caracurine V (6) and related iso-caracurine V, tetrahydrocaracurine V, and bisnortoxiferine ring systems. The compounds inhibited dissociation of the orthosteric antagonist [(3)H]N-methylscopolamine (NMS) from porcine cardiac M(2) receptors with EC(0.5,diss) values from 4 to 3270 nM. The majority of compounds hardly changed [(3)H]NMS equilibrium binding, indicating similar binding affinities in free and NMS-occupied M(2) receptors. The most potent agents were found in the caracurine V, iso-caracurine V, and tetrahydrocaracurine V series and carried nonpolar alkyl groups with a maximal chain length of three carbon atoms. 3D QSAR (CoMSIA) analysis explained the wide range of binding affinities by steric and electrostatic properties of the side chains. Furthermore, the findings suggest that the spatial orientation of the "caracurine" aromatic rings compared with the bisnortoxiferine ring skeleton is favorable to optimal allostere-receptor interactions.
authors.affiliation: Pharmaceutical Institute, University of Würzburg, Am Hubland, 97074 Würzburg, Germany. zlotos@pzlc.uni-wuerzburg.de
authors.forename: Darius P
authors.initials: DP
authors.lastname: Zlotos
authors.forename: Stefan
authors.initials: S
authors.lastname: Buller
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Stiefl
authors.forename: Knut
authors.initials: K
authors.lastname: Baumann
authors.forename: Klaus
authors.initials: K
authors.lastname: Mohr
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000495:Allosteric Site; D000818:Animals; D066298:In Vitro Techniques; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009206:Myocardium / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011869:Radioligand Assay; D043585:Receptor, Muscarinic M2 / Q000737:chemistry* / Q000378:metabolism; D013331:Strychnine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013552:Swine
chemical_list: D000470:Alkaloids; D008024:Ligands; D000644:Quaternary Ammonium Compounds; D043585:Receptor, Muscarinic M2; C488111:coracurine V; D013331:Strychnine