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Molecular Pharmacology, Vol 14, 781-786, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

Structure-Activity Relationship in a New Series of Atropine Analogs

II. The Effect of an Asymmetric N-Substituent on the Antimuscarinic Activity

S. CHERKEZ 1, H. YELLIN 1, Y. KASHMAN 2, B. YAAVETZ 3, and M. SOKOLOVSKY 3

1 "TEVA" Pharmaceutical Industries, Ltd., Tel-Aviv, Israel
2 The Chemistry Department, Tel-Aviv University, Ramat Aviv, Israel
3 The Biochemistry Department, The George S. Wise Center for Life Sciences, Tel-Aviv University, Ramat Aviv, Israel

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. KD values were calculated for the various isomers and their racemates. The order of activity was found to be RR > RS ap SR > SS. In addition, the acetates of the N-Cabc-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.

Note:
ACKNOWLEDGMENTS Valuable discussions with Prof. H. Weinstein are appreciated. Thanks are due to Miss T. Lessen and Mrs. E. Kerbis for their assistance with the syntheses.

Submitted on May 22, 1978
Accepted on May 25, 1978






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