2-(3,4-DICHLOROPHENYL)-N-METHYL-N-[2-(1-PYRROLIDINYL)-1-SUBSTITUTED-ETHYL]-ACETAMIDES - THE USE OF CONFORMATIONAL-ANALYSIS IN THE DEVELOPMENT OF A NOVEL SERIES OF POTENT OPIOID KAPPA-AGONISTS

This paper describes the synthesis of a series of N-[2-(1-pyrrolidinyl)ethyl]acetamides (1), methylated at C1 and/or C2 of the ethyl linking group, and their biological evaluation as opioid kappa-agonists. Conformational analysis of corresponding desaryl analogues 2 suggested that only those compounds capable of occupying an energy minimum close to that of the known kappa-agonist N-[2-(1-pyrrolidinyl)cyclohexyl]acetamide U-50488 might posses kappa-agonist properties. Starting from chiral amino acids, other alkyl and aryl substituents were introduced at C1 of the ethyl-linking moiety, giving compounds capable of adopting the same conformation as U-50488. The most potent of these, 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl]acetamide (8), was 146-fold more active than U-50488 in vitro in the mouse vas deferens model and exhibited potent naloxone-reversible analgesic effects (ED50 = 0.004 mg/kg sc) in an abdominal constriction model.