J-113,397 Explained

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]

Synthesis

Patents for treating arrhythmia:[12]

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

Notes and References

  1. Kawamoto H, Ozaki S, Itoh Y, Miyaji M, Arai S, Nakashima H, Kato T, Ohta H, Iwasawa Y . 6 . 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 . December 1999 . 10602690 . 10.1021/jm990517p .
  2. De Risi C, Piero Pollini G, Trapella C, Peretto I, Ronzoni S, Giardina GA . 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 . July 2001 . 11425589 . 10.1016/s0968-0896(01)00085-2 .
  3. Ozaki S, Kawamoto H, Itoh Y, Miyaji M, Iwasawa Y, Ohta H . A potent and highly selective nonpeptidyl nociceptin/orphanin FQ receptor (ORL1) antagonist: J-113397 . European Journal of Pharmacology . 387 . 3 . R17-8 . January 2000 . 10650183 . 10.1016/s0014-2999(99)00822-5 .
  4. Smith ED, Ariane Vinson N, Zhong D, Berrang BD, Catanzaro JL, Thomas JB, Navarro HA, Gilmour BP, Deschamps J, Carroll FI . 6 . 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 . January 2008 . 17976996 . 10.1016/j.bmc.2007.10.023 . 2323199 .
  5. Chung S, Pohl S, Zeng J, Civelli O, Reinscheid RK . Endogenous orphanin FQ/nociceptin is involved in the development of morphine tolerance . The Journal of Pharmacology and Experimental Therapeutics . 318 . 1 . 262–7 . July 2006 . 16595734 . 10.1124/jpet.106.103960 . 15569763 .
  6. Ozaki S, Kawamoto H, Itoh Y, Miyaji M, Azuma T, Ichikawa D, Nambu H, Iguchi T, Iwasawa Y, Ohta H . 6 . 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 . August 2000 . 10940356 . 10.1016/s0014-2999(00)00520-3 .
  7. Marti M, Mela F, Veronesi C, Guerrini R, Salvadori S, Federici M, Mercuri NB, Rizzi A, Franchi G, Beani L, Bianchi C, Morari M . 6 . 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 . July 2004 . 15282268 . 10.1523/JNEUROSCI.0987-04.2004 . 6729727 . free .
  8. Marquez P, Nguyen AT, Hamid A, Lutfy K . The endogenous OFQ/N/ORL-1 receptor system regulates the rewarding effects of acute cocaine . Neuropharmacology . 54 . 3 . 564–8 . March 2008 . 18082848 . 10.1016/j.neuropharm.2007.11.003 . 2276976 .
  9. Marti M, Trapella C, Viaro R, Morari M . 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 . February 2007 . 17287504 . 10.1523/JNEUROSCI.4346-06.2007 . 6673573 . free .
  10. Viaro R, Sanchez-Pernaute R, Marti M, Trapella C, Isacson O, Morari M . Nociceptin/orphanin FQ receptor blockade attenuates MPTP-induced parkinsonism . Neurobiology of Disease . 30 . 3 . 430–8 . June 2008 . 18413287 . 10.1016/j.nbd.2008.02.011 . 2605654 .
  11. Visanji NP, de Bie RM, Johnston TH, McCreary AC, Brotchie JM, Fox SH . 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 . October 2008 . 18759357 . 10.1002/mds.22086 . 46116472 .
  12. Guo Zheng, et al. & (2020).

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