Non-peptide ligands for opioid receptors. Design of k-specific agonists

A series of phenyl carboxy esters 5a-d derived from N-(cyclopropylmethy1)normetazocine wassynthesized and evaluated for its selectivity at p, K, and 6 opioid receptors. Compound 5a, although43 times less potent than the reference compound U50488, was specific for K receptors, having nodetectable affinity for either p or 6 receptors. Greater binding affinity was seen with thediastereoisomer having the 1'R,2'S stereochemistry in the cyclopropyl ring of the nitrogensubstituent, which was only 12 times less active than U50488. Antinociceptive activity in themouse tail flick was only slightly lower than that of U50488 (ED60 = 7.66 us 4.52 mg/kg). Naloxonefully prevented antinociception induced by (1'R,2'S)-5a at the doses of 2.0 mg/kg. Compound(1'R,2'S)-5a is one of the most K-selective non-peptide compounds reported to date. The implicationsof these results in terms of requirements for K ligands are discussed.