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

A series of phenyl carboxyl esters 5a-d derived from N-(cyclopropylmethyl)normetazocine was synthesized and evaluated for its selectivity at mu, kappa, and delta opioid receptors. Compound 5a, although 43 times less potent than the reference compound U50488, was specific for kappa receptors, having no detectable affinity for either mu or delta receptors. Greater binding affinity was seen with the diastereoisomer having the 1'R,2'S stereochemistry in the cyclopropyl ring of the nitrogen substituent, which was only 12 times less active than U50488. Antinociceptive activity in the mouse tail flick was only slightly lower than that of U50488 (ED50 = 7.66 vs 4.52 mg/kg). Naloxone fully 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 kappa-selective non-peptide compounds reported to date. The implications of these results in terms of requirements for kappa ligands are discussed.