G. Ronsisvalle et al., NONPEPTIDE LIGANDS FOR OPIOID RECEPTORS - DESIGN OF KAPPA-SPECIFIC AGONISTS, Journal of medicinal chemistry, 36(13), 1993, pp. 1860-1865
A series of phenyl carboxy esters 5a-d derived from N-(cyclopropylmeth
yl)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 recep
tors. Greater binding affinity was seen with the diastereoisomer havin
g the 1'R,2'S stereochemistry in the cyclopropyl ring of the nitrogen
substituent, which was only 12 times less active than U50488. Antinoci
ceptive 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 a
ntinociception induced by (1'R,2'S)-5a at the doses of 2.0 mg/kg. Comp
ound (1'R,2'S)-5a is one of the most kappa-selective non-peptide compo
unds reported to date. The implications of these results in terms of r
equirements for kappa ligands are discussed.