J-113,397

Last updated
J-113,397
J-113,397.svg
Clinical data
Other namesJ-113,397
Identifiers
  • 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
CompTox Dashboard (EPA)
Chemical and physical data
Formula C24H37N3O2
Molar mass 399.579 g·mol−1
3D model (JSmol)
  • C4CCCCCCC4CN(CC1CO)CCC1n3c2ccccc2n(CC)c3=O
  • 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 X mark.svgN
  • Key:MBGVUMXBUGIIBQ-LEWJYISDSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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]

Contents

Synthesis

Patents for treating arrhythmia: [12]

Improved synthesis: Additional patents: J-113,397 synthesis (2007).svg
Improved synthesis: Additional patents:

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

Related Research Articles

<span class="mw-page-title-main">Hyperalgesia</span> Abnormally increased sensitivity to pain

Hyperalgesia is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and can cause hypersensitivity to stimulus. Prostaglandins E and F are largely responsible for sensitizing the nociceptors. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.

<span class="mw-page-title-main">Etorphine</span> Semi-synthetic opioid

Etorphine (M99) is a semi-synthetic opioid possessing an analgesic potency approximately 1,000–3,000 times that of morphine. It was first prepared in 1960 from oripavine, which does not generally occur in opium poppy extract but rather the related plants Papaver orientale and Papaver bracteatum. It was reproduced in 1963 by a research group at MacFarlan Smith in Gorgie, Edinburgh, led by Kenneth Bentley. It can be produced from thebaine.

<span class="mw-page-title-main">Opioid antagonist</span> Receptor antagonist that acts on one or more of the opioid receptors

An opioid antagonist, or opioid receptor antagonist, is a receptor antagonist that acts on one or more of the opioid receptors.

<span class="mw-page-title-main">Nociceptin</span> Chemical compound

Nociceptin/orphanin FQ (N/OFQ), a 17-amino acid neuropeptide, is the endogenous ligand for the nociceptin receptor. Nociceptin acts as a potent anti-analgesic, effectively counteracting the effect of pain-relievers; its activation is associated with brain functions such as pain sensation and fear learning.

<span class="mw-page-title-main">Nociceptin receptor</span> Protein-coding gene in the species Homo sapiens

The nociceptin opioid peptide receptor (NOP), also known as the nociceptin/orphanin FQ (N/OFQ) receptor or kappa-type 3 opioid receptor, is a protein that in humans is encoded by the OPRL1 gene. The nociceptin receptor is a member of the opioid subfamily of G protein-coupled receptors whose natural ligand is the 17 amino acid neuropeptide known as nociceptin (N/OFQ). This receptor is involved in the regulation of numerous brain activities, particularly instinctive and emotional behaviors. Antagonists targeting NOP are under investigation for their role as treatments for depression and Parkinson's disease, whereas NOP agonists have been shown to act as powerful, non-addictive painkillers in non-human primates.

<span class="mw-page-title-main">Femoxetine</span> Chemical compound

Femoxetine is a drug related to paroxetine that was being developed as an antidepressant by Danish pharmaceutical company Ferrosan in 1975 before acquisition of the company by Novo Nordisk. It acts as a selective serotonin reuptake inhibitor (SSRI). Development was halted to focus attention on paroxetine instead, as femoxetine could not be administered as a daily pill.

<span class="mw-page-title-main">Alpha-2C adrenergic receptor</span> Protein-coding gene in the species Homo sapiens

The alpha-2C adrenergic receptor, also known as ADRA2C, is an alpha-2 adrenergic receptor, and also denotes the human gene encoding it.

<span class="mw-page-title-main">Metabotropic glutamate receptor 8</span> Mammalian protein found in humans

Metabotropic glutamate receptor 8 is a protein that in humans is encoded by the GRM8 gene.

<span class="mw-page-title-main">JTC-801</span> Chemical compound

JTC-801 is an opioid analgesic drug used in scientific research.

<span class="mw-page-title-main">NNC 63-0532</span> Chemical compound

NNC 63-0532 is a nociceptoid drug used in scientific research. It acts as a potent and selective agonist for the nociceptin receptor, also known as the ORL-1 receptor.

<span class="mw-page-title-main">SB-612,111</span> Chemical compound

SB-612,111 is an opioid receptor ligand which is a potent and selective antagonist for the nociceptin receptor (ORL-1), several times more potent than the older drug J-113,397. It does not have analgesic effects in its own right, but prevents the development of hyperalgesia, and also shows antidepressant effects in animal studies.

<span class="mw-page-title-main">Ro64-6198</span> Chemical compound

Ro64-6198 is an opioid drug used in scientific research. It acts as a potent and selective agonist for the nociceptin receptor, also known as the ORL-1 receptor, with over 100x selectivity over the other opioid receptors. It produces anxiolytic effects in animal studies equivalent to those of benzodiazepine drugs, but has no anticonvulsant effects and does not produce any overt effects on behaviour. However it does impair short-term memory, and counteracts stress-induced anorexia. It also has antitussive effects, and reduces the rewarding and analgesic effects of morphine, although it did not prevent the development of dependence. It has been shown to reduce alcohol self-administration in animals and suppressed relapses in animal models of alcoholism, and ORL-1 agonists may have application in the treatment of alcoholism.

<span class="mw-page-title-main">JDTic</span> Chemical compound

JDTic is a selective, long-acting ("inactivating") antagonist of the κ-opioid receptor (KOR). JDTic is a 4-phenylpiperidine derivative, distantly related structurally to analgesics such as pethidine and ketobemidone, and more closely to the MOR antagonist alvimopan. In addition, it is structurally distinct from other KOR antagonists such as norbinaltorphimine. JDTic has been used to create crystal structures of KOR [ PDB: 4DJH, 6VI4​].

<span class="mw-page-title-main">MCOPPB</span> Chemical compound

MCOPPB is a drug which acts as a potent and selective agonist for the nociceptin receptor, with a pKi of 10.07 and much weaker activity at other opioid receptors. It has only moderate affinity for the mu opioid receptor, weak affinity for the kappa opioid receptor and negligible binding at the delta opioid receptor. In animal studies, MCOPPB produces potent anxiolytic effects, with no inhibition of memory or motor function, and only slight sedative side effects which do not appear until much higher doses than the effective anxiolytic dose range.

<span class="mw-page-title-main">Cebranopadol</span> Opioid analgesic drug

Cebranopadol is an opioid analgesic of the benzenoid class which is currently under development internationally by Grünenthal, a German pharmaceutical company, and its partner Depomed, a pharmaceutical company in the United States, for the treatment of a variety of different acute and chronic pain states. As of November 2014, it is in phase III clinical trials.

<span class="mw-page-title-main">AT-076</span> Chemical compound

AT-076 is a so-called opioid "pan" antagonist and is the first reasonably balanced antagonist known of all four opioid receptor types. It acts as a silent antagonist of all four of the opioid receptors, behaving as a competitive antagonist of the μ-opioid receptor and δ-opioid receptor and as a noncompetitive antagonist of the κ-opioid receptor and nociceptin receptor. AT-076 was derived from the selective κ-opioid receptor antagonist JDTic via removal of the 3,4-dimethyl group of the trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine antagonist scaffold which increased affinity for the nociceptin receptor by 10-fold and for the μ- and δ-opioid receptors by 3-6-fold.

<span class="mw-page-title-main">SR-16435</span> Drug

SR-16435 is a drug which acts as a potent partial agonist at both the μ-opioid receptor and nociceptin receptor. In animal studies it was found to be a potent analgesic, with results suggestive of reduced development of tolerance and increased activity against neuropathic pain compared to classic μ-selective agonists.

<span class="mw-page-title-main">Sunobinop</span> Chemical compound

Sunobinop is a high affinity small molecule nociceptin receptor partial agonist.

<span class="mw-page-title-main">Ro65-6570</span> Nociceptin receptor agonist

Ro65-6570 is an opioid drug. It has a potential use in preventing the addiction to other opioids.

<span class="mw-page-title-main">SCH-221510</span> Nociceptin receptor agonist

SCH-221510 is an experimental opioid drug. It has potential as an analgesic and as a treatment to addiction of certain drugs.

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).
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.