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Chemical Compound Review

ENADOLINE     2-benzofuran-4-yl-N-methyl-N- [(5S,7S,8S)-7...

Synonyms: Enadoline HCl, SureCN122595, CI-977, CHEMBL2106706, CAM 570, ...
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Disease relevance of CI 977

  • The effect of a novel, highly potent and selective kappa-opioid receptor agonist CI-977 upon ischaemic brain damage and brain swelling has been examined in a rat model of focal cerebral ischaemia [1].
  • These data indicate that the kappa-1 opioid agonist CI-977 is neuroprotective in a model of focal cerebral ischemia in a gyrencephalic species where key systemic variables have been assessed throughout the entire post-ischemic period [2].
  • The selective kappa-opioid receptor agonist CI-977, stereoselectively antagonised clonic seizures induced by slow i.v. infusion of N-methyl-DL-aspartate in the mouse [3].
  • In the hemisphere contralateral to the occluded MCA, treatment with CI-977 (0.3 mg/kg, s.c.) 30 min prior to the induction of ischemia failed to demonstrate any significant effect on either the level of local CBF in any of the 25 regions examined or on the volume of low CBF determined by frequency distribution analysis [4].
  • The most frequently reported adverse events after CI-977 administration were dizziness, fatigue, paresthesia, headache, vasodilatation (facial flushing), emotional lability, high feeling, and abnormal thinking [5].

Psychiatry related information on CI 977


High impact information on CI 977

  • The three-dimensional structure, dynamics, and binding modes of representative kappa-opioid agonists of the arylacetamide class (U50, 488; U69,593; U62,066; CI-977; ICI199,441; ICI197,067; BRL52,537; and BRL52,656) have been investigated using molecular modeling techniques [7].
  • Systemic administration of the mu agonists, fentanyl, levorphanol, methadone, morphine, meperidine and codeine; the partial mu agonist, buprenorphine; and the kappa agonists nalorphine, bremazocine, U50488 and CI-977 was made by s.c. injection into the dorsal lymph sac of the Northern grass frog, Rana pipiens [8].
  • The electrophysiological actions of PD 129290 were also studied in rat isolated cardiac myocytes using voltage clamp [9].
  • A highly selective kappa-opioid receptor agonist, CI-977, reduces excitatory synaptic potentials in the rat locus coeruleus in vitro [10].
  • The depression of the excitatory postsynaptic potential caused by CI-977 remained in the presence of either 30 microM bicuculline and picrotoxin or when potassium acetate-filled recording electrodes were used [10].

Chemical compound and disease context of CI 977


Biological context of CI 977

  • 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)[12]
  • 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 [12].
  • The diuretic effects, pharmacokinetics, and safety of CI-977, a new centrally acting selective kappa-opioid agonist, were determined in 16 healthy subjects [5].
  • Using in situ hybridization, we have shown that the kappa-opioid receptor agonist enadoline (CI-977) and the non-competitive NMDA receptor antagonist dizocilpine (MK-901) induced the immediate early gene c-fos in dorsal medial thalamic nuclei [13].

Anatomical context of CI 977

  • CI-977 ([5R-(5a,7a,8b)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec -8-yl[-4-benzofuranacetamide monohydrochloride) caused a depression of the evoked postsynaptic potential on locus coeruleus neurons [10].
  • 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 [12].
  • Effect of the kappa-1 opioid agonist CI-977 on ischemic brain damage and cerebral blood flow after middle cerebral artery occlusion in the rat [4].
  • Subcutaneous administration of either the kappa-opioid receptor agonist enadoline (CI-977; 1 mg kg-1), or the non-competitive NMDA receptor antagonist dizocilpine (MK-801; 3 mg kg-1), at induction of ischaemia prevented neurodegeneration of CA1-CA2 pyramidal neurones in the dorsal hippocampus [14].
  • A rat brain microdialysis study of enadoline (CI-977), a k-opioid agonist, was conducted in nonanesthetized healthy rats to determine brain extracellular fluid (ECF) concentrations of CI-977 associated with neuroprotective subcutaneous (s.c.) doses [15].

Associations of CI 977 with other chemical compounds

  • The anticonvulsant action of CI-977, a selective kappa-opioid receptor agonist: a possible involvement of the glycine/NMDA receptor complex [3].
  • R-84760 was functionally 2.5 times more potent than CI-977 as a kappa-opioid receptor agonist in rabbit vas deferens [16].
  • The present study compares the electroencephalographic (EEG) and behavioural effects of highly selective kappa-opioid agonists, spiradoline (U62066), enadoline (CI-977), BRL 52656, and BRL 53001, after SC administration to conscious rats [17].
  • The purpose of this study was to unravel the active conformation of the bicyclononanones using well-known kappa-selective agonists such as ketocyclazocine, arylacetamides, several isoquinolines, CI-977, and four stereoisomers of EMD-61753 for comparison [18].

Analytical, diagnostic and therapeutic context of CI 977

  • 4. CI-977 was a potent antinociceptive agent against a mechanical noxious stimulus in rats following intravenous, intramuscular, subcutaneous and oral administration [12].
  • Subjects received single intramuscular doses of CI-977 (5, 15, or 25 micrograms) or placebo 1 week apart according to a randomized, double-blind, placebo-controlled, four-period, crossover design [5].
  • Using laser scanning confocal microscopy and the fluorescent calcium probe fluo-3, both the sustained and biphasic intracellular calcium concentration [Ca2+]i changes induced by GLU (20-40 microM) were altered by CI-977 (25-100 nM), thereby shifting the neuronal population response from unbuffered to buffered patterns of [Ca2+]i flux [11].
  • The kappa-opioid receptor agonists, CI-977 (+/-)-U-50,488H, (+/-)-bremazocine, PD-117,302, (-)-cyclazocine, and U-69,583, reversed abdominal contractions and inhibitions of gastrointestinal transit in a dose-related manner [19].
  • Three groups of 3 to 4 nonanesthetized yet restrained Sprague-Dawley rats with jugular cannulas and implanted brain (striatum) microdialysis probes received single s.c. doses of 0.3, 1.0, or 3.0 mg/kg CI-977 [15].


  1. The effect of the kappa-opioid receptor agonist CI-977 in a rat model of focal cerebral ischaemia. Kusumoto, K., Mackay, K.B., McCulloch, J. Brain Res. (1992) [Pubmed]
  2. Focal cerebral ischemia in the cat: pretreatment with a kappa-1 opioid receptor agonist, CI-977. Mackay, K.B., Kusumoto, K., Graham, D.I., McCulloch, J. Brain Res. (1993) [Pubmed]
  3. The anticonvulsant action of CI-977, a selective kappa-opioid receptor agonist: a possible involvement of the glycine/NMDA receptor complex. Singh, L., Vass, C.A., Hunter, J.C., Woodruff, G.N., Hughes, J. Eur. J. Pharmacol. (1990) [Pubmed]
  4. Effect of the kappa-1 opioid agonist CI-977 on ischemic brain damage and cerebral blood flow after middle cerebral artery occlusion in the rat. Mackay, K.B., Kusumoto, K., Graham, D.I., McCulloch, J. Brain Res. (1993) [Pubmed]
  5. Diuretic effects, pharmacokinetics, and safety of a new centrally acting kappa-opioid agonist (CI-977) in humans. Reece, P.A., Sedman, A.J., Rose, S., Wright, D.S., Dawkins, R., Rajagopalan, R. Journal of clinical pharmacology. (1994) [Pubmed]
  6. Functional implications of kappa opioid receptor-mediated modulation of glutamate transmission in the output regions of the basal ganglia in rodent and primate models of Parkinson's disease. Maneuf, Y.P., Mitchell, I.J., Crossman, A.R., Woodruff, G.N., Brotchie, J.M. Brain Res. (1995) [Pubmed]
  7. Conformational analysis and automated receptor docking of selective arylacetamide-based kappa-opioid agonists. Subramanian, G., Paterlini, M.G., Larson, D.L., Portoghese, P.S., Ferguson, D.M. J. Med. Chem. (1998) [Pubmed]
  8. Analgesic potency of mu and kappa opioids after systemic administration in amphibians. Stevens, C.W., Klopp, A.J., Facello, J.A. J. Pharmacol. Exp. Ther. (1994) [Pubmed]
  9. Electrophysiological and antiarrhythmic actions of the kappa agonist PD 129290, and its R,R (+)-enantiomer, PD 129289. Pugsley, M.K., Saint, D.A., Penz, M.P., Walker, M.J. Br. J. Pharmacol. (1993) [Pubmed]
  10. A highly selective kappa-opioid receptor agonist, CI-977, reduces excitatory synaptic potentials in the rat locus coeruleus in vitro. Pinnock, R.D. Neuroscience (1992) [Pubmed]
  11. The neuroprotective kappa-opioid CI-977 alters glutamate-induced calcium signaling in vitro. DeCoster, M.A., Conover, J.R., Hunter, J.C., Tortella, F.C. Neuroreport (1994) [Pubmed]
  12. CI-977, a novel and selective agonist for the kappa-opioid receptor. Hunter, J.C., Leighton, G.E., Meecham, K.G., Boyle, S.J., Horwell, D.C., Rees, D.C., Hughes, J. Br. J. Pharmacol. (1990) [Pubmed]
  13. Activation of c-fos mRNA in the brain by the kappa-opioid receptor agonist enadoline and the NMDA receptor antagonist dizocilpine. Panegyres, P.K., Hughes, J. Eur. J. Pharmacol. (1997) [Pubmed]
  14. Brain temperature and the neuroprotective action of enadoline and dizocilpine in the gerbil model of global ischaemia. Hayward, N.J., McKnight, A.T., Woodruff, G.N. Eur. J. Pharmacol. (1993) [Pubmed]
  15. Unbound plasma concentrations may predict neuroprotective brain concentrations: a brain microdialysis and pharmacokinetic study of enadoline in rats. Hinton, J.P., Hudson, G. Acta Neurochir. Suppl. (1999) [Pubmed]
  16. Pharmacological properties of R-84760, a novel kappa-opioid receptor agonist. Fujibayashi, K., Sakamoto, K., Watanabe, M., Iizuka, Y. Eur. J. Pharmacol. (1994) [Pubmed]
  17. Effects of highly selective kappa-opioid agonists on EEG power spectra and behavioural correlates in conscious rats. Coltro Campi, C., Clarke, G.D. Pharmacol. Biochem. Behav. (1995) [Pubmed]
  18. Search for the pharmacophore in kappa-agonistic diazabicyclo[3.3.1]nonan-9-one-1,5-diesters and arylacetamides. Brandt, W., Drosihn, S., Haurand, M., Holzgrabe, U., Nachtsheim, C. Arch. Pharm. (Weinheim) (1996) [Pubmed]
  19. Reversal by kappa-agonists of peritoneal irritation-induced ileus and visceral pain in rats. Friese, N., Chevalier, E., Angel, F., Pascaud, X., Junien, J.L., Dahl, S.G., Riviere, P.J. Life Sci. (1997) [Pubmed]
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