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J-113,397

Chemical compound

J-113,397

Chemical compound

| elimination_half-life =

(racemic)

J-113,397 is an opioid drug which was the first compound found to be a highly selective antagonist for the nociceptin receptor, also known as the ORL-1 receptor. It is several hundred times selective for the ORL-1 receptor over other opioid receptors, and its effects in animals include preventing the development of tolerance to morphine, the prevention of hyperalgesia induced by intracerebroventricular administration of nociceptin (orphanin FQ), as well as the stimulation of dopamine release in the striatum, which increases the rewarding effects of cocaine, but may have clinical application in the treatment of Parkinson's disease.

Synthesis

Patents for treating arrhythmia:

2000031061}} (to MSD KK).</ref>

Condensation between 1-Benzyl-3-methoxycarbonyl-4-piperidone [57611-47-9] (1) and O-Phenylenediamine (2) gives CID:16726310 (3). Reaction with boc anhydride followed by treatment with trifluoroacetic acid gives CID:16726358 (4). Reaction with iodoethane in the presence of base alkylates the urea nitrogen giving CID:16726359 (5). Reduction of the enamine by treatment with magnesium metal in methanol solvent occurs to give predominantly the trans isomer, CID:16726360 (6). Catalytic removal of the benzyl group gives CID:16726362 (7). Reductive amination with Cyclooctanecarbaldehyde [6688-11-5] (7) gives CID:16726364 (9). Lastly, reduction of the ester with lithium aluminium hydride completed the synthesis of J-113397 (10).

References

References

  1. (December 1999). "Discovery of the first potent and selective small molecule opioid receptor-like (ORL1) antagonist: 1-[(3R,4R)-1-cyclooctylmethyl-3- hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro-2H-benzimidazol-2-one (J-113397)". Journal of Medicinal Chemistry.
  2. (July 2001). "A new synthetic approach to 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-benzimidazol-2-one(J-113397), the first non-peptide ORL-1 receptor antagonist". Bioorganic & Medicinal Chemistry.
  3. (January 2000). "A potent and highly selective nonpeptidyl nociceptin/orphanin FQ receptor (ORL1) antagonist: J-113397". European Journal of Pharmacology.
  4. (January 2008). "A new synthesis of the ORL-1 antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) and activity in a calcium mobilization assay". Bioorganic & Medicinal Chemistry.
  5. (July 2006). "Endogenous orphanin FQ/nociceptin is involved in the development of morphine tolerance". The Journal of Pharmacology and Experimental Therapeutics.
  6. (August 2000). "In vitro and in vivo pharmacological characterization of J-113397, a potent and selective non-peptidyl ORL1 receptor antagonist". European Journal of Pharmacology.
  7. (July 2004). "Blockade of nociceptin/orphanin FQ receptor signaling in rat substantia nigra pars reticulata stimulates nigrostriatal dopaminergic transmission and motor behavior". The Journal of Neuroscience.
  8. (March 2008). "The endogenous OFQ/N/ORL-1 receptor system regulates the rewarding effects of acute cocaine". Neuropharmacology.
  9. (February 2007). "The nociceptin/orphanin FQ receptor antagonist J-113397 and L-DOPA additively attenuate experimental parkinsonism through overinhibition of the nigrothalamic pathway". The Journal of Neuroscience.
  10. (June 2008). "Nociceptin/orphanin FQ receptor blockade attenuates MPTP-induced parkinsonism". Neurobiology of Disease.
  11. (October 2008). "The nociceptin/orphanin FQ (NOP) receptor antagonist J-113397 enhances the effects of levodopa in the MPTP-lesioned nonhuman primate model of Parkinson's disease". Movement Disorders.
  12. Guo Zheng, et al. {{Cite patent. CN. 111249279 & {{Cite patent. CN. 111265663 (2020).
  13. (2 May 2007). "A New Approach to the Synthesis of the Nonpeptide NOP Receptor Antagonist J-113397". Synthesis.
  14. Satoshi Ozaki, et al. {{Cite patent. WO. 1998054168 (to MSD KK).
  15. Hiroshi Kawamoto, et al. {{Cite patent. WO. 2000031061 (to MSD KK).
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synthetic-opioids benzimidazoles piperidines ureas primary-alcohols nociceptin-receptor-antagonists
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