Kinetic studies on muscarinic antagonist-agonist competition

The kinetics of the association and dissociation of the radiolabeled high affinity muscarinic antagonist N-[3H]methyl-4-piperidinyl benzilate was studied with the receptor from smooth muscle. Neither the agonists carbamylcholine and oxotremorine nor the antagonist atropine did influence the dissociation rate (k-2) of the receptor . antagonist complex. Binding of the antagonist (A) takes place in two consecutive steps: (formula: see text). Agonists did not seem to influence the dissociation constant (k-1/k+1) of the first binding step, while atropine caused a large increase in this constant. These results indicate that while antagonist-antagonist competition can be explained in terms of competition for the free receptor (R), antagonist-agonist competition cannot be fitted with such a simple model.