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Conformationally constrained bicyclic derivatives of the potent and selective κ-opioid receptor agonist 2-(3,4-dichlorophenyl)-N-methyl-N- [(1S)-1-phenyl-2- (1-pyrrolidinyl)-ethyl] acetam~ide (3, ICI-199, 441) were designed to explore the effect of the conformational restriction and stereochemistry of the pharmacophoric ethylenediamine incorporated into the pyrrolidine on the affinity and κ-selectivity. A facile enantiospecific synthetic route was established to afford all four stereoisomers starting from readily available amino acids through mild cyclization and amide formation.
Conformationally constrained bicyclic derivatives of the potent and selective κ-opioid receptor agonist 2- (3,4-dichlorophenyl) -N-methyl-N- [(1S) -1 -phenyl- ~ ide (3, ICI-199, 441) were designed to explore the effect of the conformational restriction and stereochemistry of the pharmacophoric ethylenediamine incorporated into the pyrrolidine on the affinity and κ-selectivity. A facile enantiospecific synthetic route was established to afford all four stereoisomers starting from sufficiently available amino acids through mild cyclization and amide formation.