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

A series of phenyl carboxyl esters 5a-d derived fromN-(cyclopropylmethyl)normetazocine was synthesized and evaluated for itsselectivity at mu, kappa, and delta opioid receptors. Compound 5a, although 43times less potent than the reference compound U50488, was specific for kappareceptors, having no detectable affinity for either mu or delta receptors.Greater binding affinity was seen with the diastereoisomer having the 1'R,2'Sstereochemistry in the cyclopropyl ring of the nitrogen substituent, which wasonly 12 times less active than U50488. Antinociceptive activity in the mouse tailflick 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-peptidecompounds reported to date. The implications of these results in terms ofrequirements for kappa ligands are discussed.