CI‐977, a novel and selective agonist for the κ‐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 [ 3 H]‐U69593‐labelled κ‐sites ( K i = 0.11 n m ) but with low affinity to [ 3 H]‐[ d ‐Ala 2 , MePhe 4 , Glyol 5 ] enkephalin (DAMGO) labelled μ‐sites ( K i = 99n m ) and [ 3 H]‐[ d ‐Pen 2,5 ]enkephalin (DPDPE) labelled δ‐sites ( K i = 1.04 μ m ). CI‐977 also bound with negligible affinity to [ 3 H]‐(+)‐3‐(1‐propyl‐3‐piperidinyl)phenol (3‐PPP) labelled σ‐sites ( K i = 1.9 μ m ) and [ 3 H]‐1‐(1‐[2‐thienyl]cyclohexyl)piperidine (TCP) labelled PCP sites ( K i > 10 μ m ). 3 CI‐977 produced a potent inhibition of the electrically‐evoked contractions of the guinea‐pig ileum and rabbit vas deferens with IC 50 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 at the κ‐opioid receptor.