Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1990 Sep;101(1):183–189. doi: 10.1111/j.1476-5381.1990.tb12110.x

CI-977, a novel and selective agonist for the kappa-opioid receptor.

J C Hunter 1, G E Leighton 1, K G Meecham 1, S J Boyle 1, D C Horwell 1, D C Rees 1, J Hughes 1
PMCID: PMC1917616  PMID: 2178014

Abstract

1. CI-977 is a new, nonpeptide kappa-opioid compound that has been synthesized and its pharmacological properties determined in a series of in vitro and in vivo rodent models. 2. In a radioligand binding studies, with guinea-pig forebrain homogenates, CI-977 bound with high affinity to [3H]-U69593-labelled kappa-sites (Ki = 0.11 nM) but with low affinity to [3H]-[D-Ala2, MePhe4, Gly-ol5] enkephalin (DAMGO) labelled mu-sites (Ki = 99 nM) and [3H]-[D-Pen2.5]enkephalin (DPDPE) labelled delta-sites (Ki = 1.04 microM). CI-977 also bound with negligible affinity to [3H]-(+)-3-(1-propyl-3-piperi-dinyl)phenol (3-PPP) labelled sigma-sites (Ki = 1.9 microM) and [3H]-1-(1-[2-thienyl]cyclohexyl)piperidine (TCP) labelled PCP sites (Ki greater than 10 microM). 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 pKB values for the opioid antagonists naloxone (7.6) and norbinaltorphimine (10.5) supported the kappa 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
183

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ARUNLAKSHANA O., SCHILD H. O. Some quantitative uses of drug antagonists. Br J Pharmacol Chemother. 1959 Mar;14(1):48–58. doi: 10.1111/j.1476-5381.1959.tb00928.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Birch P. J., Hayes A. G., Sheehan M. J., Tyers M. B. Norbinaltorphimine: antagonist profile at kappa opioid receptors. Eur J Pharmacol. 1987 Dec 15;144(3):405–408. doi: 10.1016/0014-2999(87)90397-9. [DOI] [PubMed] [Google Scholar]
  3. Cheng Y., Prusoff W. H. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol. 1973 Dec 1;22(23):3099–3108. doi: 10.1016/0006-2952(73)90196-2. [DOI] [PubMed] [Google Scholar]
  4. Clark C. R., Birchmore B., Sharif N. A., Hunter J. C., Hill R. G., Hughes J. PD117302: a selective agonist for the kappa-opioid receptor. Br J Pharmacol. 1988 Mar;93(3):618–626. doi: 10.1111/j.1476-5381.1988.tb10319.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Costello G. F., Main B. G., Barlow J. J., Carroll J. A., Shaw J. S. A novel series of potent and selective agonists at the opioid kappa-receptor. Eur J Pharmacol. 1988 Jul 14;151(3):475–478. doi: 10.1016/0014-2999(88)90546-8. [DOI] [PubMed] [Google Scholar]
  6. DeLean A., Munson P. J., Rodbard D. Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol. 1978 Aug;235(2):E97–102. doi: 10.1152/ajpendo.1978.235.2.E97. [DOI] [PubMed] [Google Scholar]
  7. Dykstra L. A., Gmerek D. E., Winger G., Woods J. H. Kappa opioids in rhesus monkeys. I. Diuresis, sedation, analgesia and discriminative stimulus effects. J Pharmacol Exp Ther. 1987 Aug;242(2):413–420. [PubMed] [Google Scholar]
  8. Gillan M. G., Kosterlitz H. W. Spectrum of the mu, delta- and kappa-binding sites in homogenates of rat brain. Br J Pharmacol. 1982 Nov;77(3):461–469. doi: 10.1111/j.1476-5381.1982.tb09319.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hutchinson M., Kosterlitz H. W., Leslie F. M., Waterfield A. A. Assessment in the guinea-pig ileum and mouse vas deferens of benzomorphans which have strong antinociceptive activity but do not substitute for morphine in the dependent monkey. Br J Pharmacol. 1975 Dec;55(4):541–546. doi: 10.1111/j.1476-5381.1975.tb07430.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kenakin T. P. The relative contribution of affinity and efficacy to agonist activity: organ selectivity of noradrenaline and oxymetazoline with reference to the classification of drug receptors. Br J Pharmacol. 1984 Jan;81(1):131–141. doi: 10.1111/j.1476-5381.1984.tb10753.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kosterlitz H. W., Paterson S. J., Robson L. E. Characterization of the kappa-subtype of the opiate receptor in the guinea-pig brain. Br J Pharmacol. 1981 Aug;73(4):939–949. doi: 10.1111/j.1476-5381.1981.tb08749.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lahti R. A., Mickelson M. M., McCall J. M., Von Voigtlander P. F. [3H]U-69593 a highly selective ligand for the opioid kappa receptor. Eur J Pharmacol. 1985 Feb 26;109(2):281–284. doi: 10.1016/0014-2999(85)90431-5. [DOI] [PubMed] [Google Scholar]
  13. Leander J. D. A kappa opioid effect: increased urination in the rat. J Pharmacol Exp Ther. 1983 Jan;224(1):89–94. [PubMed] [Google Scholar]
  14. Leighton G. E., Johnson M. A., Meecham K. G., Hill R. G., Hughes J. Pharmacological profile of PD 117302, a selective kappa-opioid agonist. Br J Pharmacol. 1987 Dec;92(4):915–922. doi: 10.1111/j.1476-5381.1987.tb11398.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Martin W. R., Eades C. G., Thompson J. A., Huppler R. E., Gilbert P. E. The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther. 1976 Jun;197(3):517–532. [PubMed] [Google Scholar]
  16. Martin W. R. Pharmacology of opioids. Pharmacol Rev. 1983 Dec;35(4):283–323. [PubMed] [Google Scholar]
  17. Meecham K. G., Boyle S. J., Hunter J. C., Hughes J. An in vitro profile of activity for the (+) and (-) enantiomers of spiradoline and PD117302. Eur J Pharmacol. 1989 Dec 7;173(2-3):151–157. doi: 10.1016/0014-2999(89)90512-8. [DOI] [PubMed] [Google Scholar]
  18. Miller L., Shaw J. S., Whiting E. M. The contribution of intrinsic activity to the action of opioids in vitro. Br J Pharmacol. 1986 Mar;87(3):595–601. doi: 10.1111/j.1476-5381.1986.tb10202.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Peters G. R., Ward N. J., Antal E. G., Lai P. Y., deMaar E. W. Diuretic actions in man of a selective kappa opioid agonist: U-62,066E. J Pharmacol Exp Ther. 1987 Jan;240(1):128–131. [PubMed] [Google Scholar]
  20. Pfeiffer A., Brantl V., Herz A., Emrich H. M. Psychotomimesis mediated by kappa opiate receptors. Science. 1986 Aug 15;233(4765):774–776. doi: 10.1126/science.3016896. [DOI] [PubMed] [Google Scholar]
  21. Portoghese P. S., Lipkowski A. W., Takemori A. E. Binaltorphimine and nor-binaltorphimine, potent and selective kappa-opioid receptor antagonists. Life Sci. 1987 Mar 30;40(13):1287–1292. doi: 10.1016/0024-3205(87)90585-6. [DOI] [PubMed] [Google Scholar]
  22. Shearman G. T., Stenfors C. Bremazocine-induced backwards walking behavior in rats is mediated via opioid kappa receptors. Pharmacol Biochem Behav. 1986 Apr;24(4):861–863. doi: 10.1016/0091-3057(86)90426-0. [DOI] [PubMed] [Google Scholar]
  23. Shippenberg T. S., Stein C., Huber A., Millan M. J., Herz A. Motivational effects of opioids in an animal model of prolonged inflammatory pain: alteration in the effects of kappa- but not of mu-receptor agonists. Pain. 1988 Nov;35(2):179–186. doi: 10.1016/0304-3959(88)90225-4. [DOI] [PubMed] [Google Scholar]
  24. Smith J. A., Hunter J. C., Hill R. G., Hughes J. A kinetic analysis of kappa-opioid agonist binding using the selective radioligand [3H]U69593. J Neurochem. 1989 Jul;53(1):27–36. doi: 10.1111/j.1471-4159.1989.tb07291.x. [DOI] [PubMed] [Google Scholar]
  25. Steinfels G. F., Alberici G. P., Tam S. W., Cook L. Biochemical, behavioral, and electrophysiologic actions of the selective sigma receptor ligand (+)-pentazocine. Neuropsychopharmacology. 1988 Dec;1(4):321–327. [PubMed] [Google Scholar]
  26. Su T. P. Evidence for sigma opioid receptor: binding of [3H]SKF-10047 to etorphine-inaccessible sites in guinea-pig brain. J Pharmacol Exp Ther. 1982 Nov;223(2):284–290. [PubMed] [Google Scholar]
  27. Tam S. W. Naloxone-inaccessible sigma receptor in rat central nervous system. Proc Natl Acad Sci U S A. 1983 Nov;80(21):6703–6707. doi: 10.1073/pnas.80.21.6703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Tyers M. B. A classification of opiate receptors that mediate antinociception in animals. Br J Pharmacol. 1980 Jul;69(3):503–512. doi: 10.1111/j.1476-5381.1980.tb07041.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ukai M., Kameyama T. Multi-dimensional analyses of behavior in mice treated with U-50,488H, a purported kappa (non-mu) opioid agonist. Brain Res. 1985 Jul 1;337(2):352–356. doi: 10.1016/0006-8993(85)90074-5. [DOI] [PubMed] [Google Scholar]
  30. Verlinde C., De Ranter C. Assessment of the kappa-opioid activity of a series of 6,7-benzomorphans in the rabbit vas deferens. Eur J Pharmacol. 1988 Aug 9;153(1):83–87. doi: 10.1016/0014-2999(88)90590-0. [DOI] [PubMed] [Google Scholar]
  31. Vonvoigtlander P. F., Lahti R. A., Ludens J. H. U-50,488: a selective and structurally novel non-Mu (kappa) opioid agonist. J Pharmacol Exp Ther. 1983 Jan;224(1):7–12. [PubMed] [Google Scholar]
  32. Vonvoigtlander P. F., Lewis R. A. Analgesic and mechanistic evaluation of spiradoline, a potent kappa opioid. J Pharmacol Exp Ther. 1988 Jul;246(1):259–262. [PubMed] [Google Scholar]
  33. Zukin R. S., Zukin S. R. Demonstration of [3H]cyclazocine binding to multiple opiate receptor sites. Mol Pharmacol. 1981 Sep;20(2):246–254. [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES