Abstract

The dissociation constants (K_A) and the relative intrinsic efficacies (ε) of lactoylcholines and related compounds were determined on the longitudinal muscle of the guinea-pig ileum (for muscarinic activity) and the frog rectus abdominis muscle (for nicotinic activity). The K_AS of these agonists at muscarinic receptors increase in the following order: acetyl- < propionyl- < acryloyl- ≤ D-lactoyl- ≤ DL-lactoyl- < L-lactoylcholines. Their εS at the muscarinic receptors have the following order: acetyl- > propionyl- > acryloyl- = D-lactoyl- = DL-lactoyl- = L-lactoylcholines. An increase in the size of the acyl group among these choline esters decreases the affinity and the ε at muscarinic receptors. The difference in the muscarinic potencies of D- and L-lactoylcholines is due to the difference in their affinities. K_AS at nicotinic receptors increase in this order: acetyl- ≤ propionyl- ≤ acryloyl- D-lactoyl- < DL-lactoyl < L-lactoylcholine. All of these compounds have the same εS. The charge on the carbonyl-carbon of these choline esters contributes to their affinities at the nicotinic receptors. There is an apparent linear relationship between the negative logarithm of the ED5O and the negative logarithm of the K_A among these compounds. Whereas both types of cholinergic receptors are specific for D-lactoylcholine, cholinesterases are stereospecific for L-lactoylcholines. There is no significant difference between K_AS of acetyicholine at muscarinic and nicotinic receptors. Other choline esters exhibited significant differences in their K_AS at these receptors. Muscarinic and nicotinic receptors may be termed as isoceptors (receptors with close similarities in the critical active site area but with differences in the environment of the areas adjacent to active sites) with significant differences in the environment of the site 2 where at least one of the oxygen atoms of a choline ester interacts for inducing the pharmacological effect.