2-(3,4-Dichlorophenyl)-N-methyl-N-acetamides: The Use of Conformational Analysis in the Development of a Novel Series of Potent Opioid κ Agonists

Article abstract of DOI:10.1021/jm00105a027

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 κ 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 κ agonist N-<2-(1-pyrrolidinyl)cyclohexyl>acetamide U-50488 might possess κ 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)ethyl>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.