title: The allosteric interaction of otenzepad (AF-DX 116) at muscarinic M2 receptors in guinea pig atria.
abstract: The effects of the muscarinic receptor antagonist, otenzepad, in combination with the competitive antagonists N-methylscopolamine, dexetimide and atropine, or the allosteric modulators, C(7)/3'-phth, gallamine and alcuronium, were measured in the guinea pig electrically driven left atrium using the agonists, carbachol or acetylcholine. Otenzepad, in combination with C(7)/3'-phth or gallamine, gave concentration-ratios close to additive and in agreement with theoretical model predictions for combination of two allosteric modulators acting at a common site. However, when otenzepad was combined with alcuronium, dexetimide or N-methylscopolamine, supra-additive effects were observed. For either competitive antagonist in combination with otenzepad, the degree of supra-additivity was more evident after 2-h equilibration than after 40 min. When otenzepad was combined with atropine, no supra-additivity was observed with carbachol as the agonist, but was evident with acetylcholine. Otenzepad was also unable to fully inhibit [3H]N-methylscopolamine binding when the radioligand was employed at a concentration of approximately 100 x K(D). It is concluded that the action of otenzepad involves an allosteric site and a number of possibilities are discussed for its location.
authors: Department of Pharmaceutical Biology and Pharmacology, Victorian College of Pharmacy (Monash University), 381 Royal Parade, Victoria 3052, Parkville, Australia
authors: A
authors: A
authors: Lanzafame
authors: A
authors: A
authors: Christopoulos
authors: F
authors: F
authors: Mitchelson
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D003909:Dexetimide / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D005703:Gallamine Triethiodide / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D019832:N-Methylscopolamine / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010276:Parasympatholytics / Q000494:pharmacology*; D010797:Phthalimides / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D011869:Radioligand Assay; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; D018727:Muscarinic Antagonists; D018733:Nicotinic Antagonists; D010276:Parasympatholytics; D010797:Phthalimides; D000644:Quaternary Ammonium Compounds; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; C116689:heptane-1,7-bis-(dimethyl-3'-phthalimidopropyl)ammonium bromide; D010890:Pirenzepine; D003909:Dexetimide; D001285:Atropine; D002217:Carbachol; D000109:Acetylcholine; C048593:otenzepad; D005703:Gallamine Triethiodide; D019832:N-Methylscopolamine