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CI‐977, a novel and selective agonist for the κ‐opioid receptor
Author(s) -
Hunter J.C.,
Leighton G.E.,
Meecham K.G.,
Boyle S.J.,
Horwell D.C.,
Rees D.C.,
Hughes J.
Publication year - 1990
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1990.tb12110.x
Subject(s) - chemistry , agonist , enkephalin , damgo , pharmacology , opioid , endocrinology , medicine , vas deferens , (+) naloxone , guinea pig , receptor , stereochemistry , biochemistry
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.