Structure-activity relationship in a new series of atropine analogs. II. The effect of an asymmetric N-substituent on the antimuscarinic activity

A new series of atropine analogs, in which an asymmetric center was introduced onto the N-atom in addition to that existing in the ester moiety, was prepared. The anti-muscarinic potency of the drugs was evaluated in the guinea-pig ileum test and compared to that of atropine itself. All the drugs tested inhibited competitively the acetylcholine-induced contractions. K(D) values were calculated for the various isomers and their racemates. The order of activity was found to be RR > nearly equal to SR > SS. In addition, the acetates of the N-C(abc)-substituted analogs were also found to possess a weak anti-muscarinic activity. These results are discussed in terms of the contribution of both the nitrogen and ester sites to the recognition process of the muscarinic pharmacophore.