The allosteric interaction of otenzepad (AF-DX 116) at muscarinic M2 receptors in guinea pig atria |
| |
Authors: | Lanzafame A Christopoulos A Mitchelson F |
| |
Affiliation: | Department of Pharmaceutical Biology and Pharmacology, Victorian College of Pharmacy (Monash University), 381 Royal Parade, Victoria 3052, Parkville, Australia |
| |
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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|