J-113,397

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.[1][2] It is several hundred times selective for the ORL-1 receptor over other opioid receptors,[3][4] and its effects in animals include preventing the development of tolerance to morphine,[5] the prevention of hyperalgesia induced by intracerebroventricular administration of nociceptin (orphanin FQ),[6] as well as the stimulation of dopamine release in the striatum,[7] which increases the rewarding effects of cocaine,[8] but may have clinical application in the treatment of Parkinson's disease.[9][10][11]

J-113,397
Clinical data
Other namesJ-113,397
Identifiers
IUPAC name
  • 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro-2H-benzimidazol-2-one
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC24H37N3O2
Molar mass399.579 g·mol−1
3D model (JSmol)
SMILES
  • C4CCCCCCC4CN(CC1CO)CCC1n3c2ccccc2n(CC)c3=O
InChI
  • InChI=1S/C24H37N3O2/c1-2-26-22-12-8-9-13-23(22)27(24(26)29)21-14-15-25(17-20(21)18-28)16-19-10-6-4-3-5-7-11-19/h8-9,12-13,19-21,28H,2-7,10-11,14-18H2,1H3/t20-,21+/m0/s1 N
  • Key:MBGVUMXBUGIIBQ-LEWJYISDSA-N N
 NY (what is this?)  (verify)

Synthesis

Patents for treating arrhythmia:[12]

Improved synthesis:[13] Additional patents:[14][15]

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).

See also

References
  1. Kawamoto H, Ozaki S, Itoh Y, Miyaji M, Arai S, Nakashima H, et al. (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. 42 (25): 5061–3. doi:10.1021/jm990517p. PMID 10602690.
  2. De Risi C, Piero Pollini G, Trapella C, Peretto I, Ronzoni S, Giardina GA (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. 9 (7): 1871–7. doi:10.1016/s0968-0896(01)00085-2. PMID 11425589.
  3. Ozaki S, Kawamoto H, Itoh Y, Miyaji M, Iwasawa Y, Ohta H (January 2000). "A potent and highly selective nonpeptidyl nociceptin/orphanin FQ receptor (ORL1) antagonist: J-113397". European Journal of Pharmacology. 387 (3): R17-8. doi:10.1016/s0014-2999(99)00822-5. PMID 10650183.
  4. Smith ED, Ariane Vinson N, Zhong D, Berrang BD, Catanzaro JL, Thomas JB, et al. (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. 16 (2): 822–9. doi:10.1016/j.bmc.2007.10.023. PMC 2323199. PMID 17976996.
  5. Chung S, Pohl S, Zeng J, Civelli O, Reinscheid RK (July 2006). "Endogenous orphanin FQ/nociceptin is involved in the development of morphine tolerance". The Journal of Pharmacology and Experimental Therapeutics. 318 (1): 262–7. doi:10.1124/jpet.106.103960. PMID 16595734. S2CID 15569763.
  6. Ozaki S, Kawamoto H, Itoh Y, Miyaji M, Azuma T, Ichikawa D, et al. (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. 402 (1–2): 45–53. doi:10.1016/s0014-2999(00)00520-3. PMID 10940356.
  7. Marti M, Mela F, Veronesi C, Guerrini R, Salvadori S, Federici M, et al. (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. 24 (30): 6659–66. doi:10.1523/JNEUROSCI.0987-04.2004. PMC 6729727. PMID 15282268.
  8. Marquez P, Nguyen AT, Hamid A, Lutfy K (March 2008). "The endogenous OFQ/N/ORL-1 receptor system regulates the rewarding effects of acute cocaine". Neuropharmacology. 54 (3): 564–8. doi:10.1016/j.neuropharm.2007.11.003. PMC 2276976. PMID 18082848.
  9. Marti M, Trapella C, Viaro R, Morari M (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. 27 (6): 1297–307. doi:10.1523/JNEUROSCI.4346-06.2007. PMC 6673573. PMID 17287504.
  10. Viaro R, Sanchez-Pernaute R, Marti M, Trapella C, Isacson O, Morari M (June 2008). "Nociceptin/orphanin FQ receptor blockade attenuates MPTP-induced parkinsonism". Neurobiology of Disease. 30 (3): 430–8. doi:10.1016/j.nbd.2008.02.011. PMC 2605654. PMID 18413287.
  11. Visanji NP, de Bie RM, Johnston TH, McCreary AC, Brotchie JM, Fox SH (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. 23 (13): 1922–5. doi:10.1002/mds.22086. PMID 18759357. S2CID 46116472.
  12. Guo Zheng, et al. CN 111249279 & CN 111265663 (2020).
  13. Sulima, A., Folk, J., Jacobson, A., Rice, K. (2 May 2007). "A New Approach to the Synthesis of the Nonpeptide NOP Receptor Antagonist J-113397". Synthesis. 2007 (10): 1547–1553. doi:10.1055/s-2007-966037.
  14. Satoshi Ozaki, et al. WO 1998054168 (to MSD KK).
  15. Hiroshi Kawamoto, et al. WO 2000031061 (to MSD KK).
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