In vivo and in vitro studies on the antimuscarinic activity of some amino esters of benzilic acid

The cholinergic antimuscarinic properties of some aliphatic and heterocyclic aminoesters of benzilic acid were evaluated in the CNS as well as in peripheral organs. Antagonism to hypothermia and to forced motor activity disturbances, both centrally mediated and induced in mice by oxotremorine, was kinetically determined in vivo. The antiacetylcholine activity of these compounds on the isolated guinea pig ileum, and their affinity for muscarinic high-affinity binding-sites in mouse brain homogenate were determined and correlated in vitro. 3-Quinuclidinyl benzilate (QNB) was found to be the most potent drug in vivo as well as in vitro, while dimethylaminoethyl benzilate was the least active. Atropine was as potent as scopolamine in the competition experiments in vitro but ten times less active in the two in vivo tests. Rate constants for the onset (k_on) and offset (k_off) of the antimuscarinic activity determined on the isolateed ileum, were found to increase and decrease, respectively, with the increase in the affinity of the drugs for the muscarinic binding-sites. The relationship between the molecular structure and the properties of these compounds is discussed in terms of the factors contributing to the observed rate constants of antimuscarinic activity and of the reasons for the decrease in the apparent potency of atropine in vivo.