title: Synthesis and muscarinic receptors affinity of a series of antagonist bivalent ligands.
abstract: A series of bivalent ligands (2-8) derived from 2,2-diphenyl-[1,3]-dioxolan-4-ylmethyl-dimethylamine methiodide 1 has been synthesized and tested to evaluate affinity and selectivity for M1, M2 and M3 muscarinic receptor subtypes. In order to study the contribution of the spacer and of a second cationic head to the binding process, unsymmetrical ligands (9,10) have also been prepared. The results, expressed in terms of pA2 values, show that, although the spacer negatively affects the interaction of the bivalent ligands with the three receptor subtypes, affinity and selectivity are modulated by its length; this indicates that the pharmacophore binding sites are organized differently with respect to their mutual proximity and orientation, in each receptor subtype.
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Camerino.
authors.forename: A
authors.initials: A
authors.lastname: Piergentili
authors.forename: W
authors.initials: W
authors.lastname: Quaglia
authors.forename: S K
authors.initials: SK
authors.lastname: Tayebati
authors.forename: F
authors.initials: F
authors.lastname: Paparelli
authors.forename: L
authors.initials: L
authors.lastname: Malmusi
authors.forename: L
authors.initials: L
authors.lastname: Brasili
mesh_terms: D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D016275:Atrial Function; D002217:Carbachol / Q000494:pharmacology; D004148:Dioxolanes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004558:Electric Stimulation; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008024:Ligands; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D010276:Parasympatholytics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000378:metabolism*; D014649:Vas Deferens / Q000187:drug effects
chemical_list: C087747:2,2-diphenyl-(1,3)-dioxolan-4-ylmethyl(dimethyl)amine methiodide; D004148:Dioxolanes; D008024:Ligands; D010276:Parasympatholytics; D011976:Receptors, Muscarinic; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; D002217:Carbachol