CI-977, A NOVEL AND SELECTIVE AGONIST FOR THE KAPPA-OPIOID RECEPTOR

1. CI-977 is a new, nonpeptide κ-opioid compound that has been synthesized and its pharmacological properties determined in a series of in vitro and in vivo rodent models. 2. In radioligand binding studies, with guinea-pig forebrain homogenates, CI-977 bound with high affinity to [3H]-U69593-labelled κ-sites (K(i) = 0.11 nM) but with low affinity to [3H]-[D-Ala2, MePhe4, Gly-ol5] enkephalin (DAMGO) labelled μ-sites (K(i) = 99 nM) and [3H]-[D-Pen2,5]enkephalin (DPDPE) labelled δ-sites (K(i) = 1.04 μM). CI-977 also bound with negligible affinity to [3H]-(+)-3-(1-propyl-3-piperidinyl)phenol (3-PPP) labelled σ-sites (K(i) = 1.9 μM) and [3H]-1-(1-[2-thienyl]cyclohexyl)piperidine (TCP) labelled PCP sites (K(i) > 10 μM). 3. CI-977 produced a potent inhibition of the electrically-evoked contractions of the guinea-pig ileum and rabbit vas deferens with IC50 values of 0.087 nM and 3.3 nM, respectively. The pK(B) values for the opioid antagonists naloxone (7.6) and norbinaltorphimine (10.5) supported the κ nature of the CI-977-mediated effects in the smooth muscle assays. 4. CI-977 was a potent antinociceptive agent against a mechanical noxious stimulus in rats following intravenous, intramuscular, subcutaneous and oral administration. CI-977 was also effective against mechanical and chemical noxious stimuli in the mouse but ineffective against a thermal stimulus. The antinociceptive effects produced by CI-977 were completely reversed by naloxone (1 mg kg-1, s.c.). 5. At doses close to those required to produce antinociception, CI-977 also caused a naloxone-reversible diuresis and inhibition of locomotor activity. 6. The in vitro and in vivo pharmacological profile of CI-977 demonstrates that it is a potent and selective agonist as the κ-opioid receptor.