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Tebanicline

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Tebanicline
Clinical data
ATC code
  • none
Identifiers
  • 5-{[(2R)-Azetidin-2-yl]methoxy}-2-chloropyridine
CAS Number
PubChemCID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.207.679Edit this at Wikidata
Chemical and physical data
FormulaC9H11ClN2O
Molar mass198.65g·mol−1
3D model (JSmol)
  • C1CN[C@H]1COC2=CN=C(C=C2)Cl
  • InChI=1S/C9H11ClN2O/c10-9-2-1-8(5-12-9)13-6-7-3-4-11-7/h1-2,5,7,11H,3-4,6H2/t7-/m1/s1☒N
  • Key:MKTAGSRKQIGEBH-SSDOTTSWSA-N☒N
☒NcheckY(what is this?)(verify)

Tebanicline(ebanicline,ABT-594) is a potent synthetic nicotinic (non-opioid) analgesic drug developed byAbbott.It was developed as a less toxicanalogof the potentpoison dart frog-derived compoundepibatidine,which is about 200 times stronger thanmorphineas ananalgesic,but produces extremely dangerous toxic side effects.[1][2]Like epibatidine, tebanicline showed potent analgesic activity againstneuropathic painin both animal and human trials, but with far less toxicity than its parent compound.[3][4][5][6][7][8]It acts as apartial agonistat neuronalnicotinic acetylcholine receptors,binding to both theα3β4and theα4β2subtypes.[9]

Tebanicline progressed to Phase II clinical trials in humans,[10]but was dropped from further development due to unacceptable incidence ofgastrointestinalside effects.[11]However, further research in this area is ongoing,[12][13][14][15]and the development of nicotinic acetylcholine receptor agonists is ongoing.[16][17][18][19]No agents from this class have successfully completed human clinical trials due to their unacceptable side effect profiles. Research in the area continues.[20]

References

[edit]
  1. ^Bannon AW, Decker MW, Holladay MW, Curzon P, Donnelly-Roberts D, Puttfarcken PS, et al. (January 1998). "Broad-spectrum, non-opioid analgesic activity by selective modulation of neuronal nicotinic acetylcholine receptors".Science.279(5347): 77–81.Bibcode:1998Sci...279...77B.doi:10.1126/science.279.5347.77.PMID9417028.
  2. ^Holladay MW, Wasicak JT, Lin NH, He Y, Ryther KB, Bannon AW, et al. (February 1998). "Identification and initial structure-activity relationships of (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), a potent, orally active, non-opiate analgesic agent acting via neuronal nicotinic acetylcholine receptors".Journal of Medicinal Chemistry.41(4): 407–12.doi:10.1021/jm9706224.PMID9484491.
  3. ^Donnelly-Roberts DL, Puttfarcken PS, Kuntzweiler TA, Briggs CA, Anderson DJ, Campbell JE, et al. (May 1998)."ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective analgesic acting via neuronal nicotinic acetylcholine receptors: I. In vitro characterization".The Journal of Pharmacology and Experimental Therapeutics.285(2): 777–86.PMID9580626.
  4. ^Bannon AW, Decker MW, Curzon P, Buckley MJ, Kim DJ, Radek RJ, et al. (May 1998)."ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective antinociceptive agent acting via neuronal nicotinic acetylcholine receptors: II. In vivo characterization".The Journal of Pharmacology and Experimental Therapeutics.285(2): 787–94.PMID9580627.
  5. ^Decker MW, Bannon AW, Buckley MJ, Kim DJ, Holladay MW, Ryther KB, et al. (April 1998). "Antinociceptive effects of the novel neuronal nicotinic acetylcholine receptor agonist, ABT-594, in mice".European Journal of Pharmacology.346(1): 23–33.doi:10.1016/S0014-2999(98)00042-9.PMID9617748.
  6. ^Kesingland AC, Gentry CT, Panesar MS, Bowes MA, Vernier JM, Cube R, et al. (May 2000). "Analgesic profile of the nicotinic acetylcholine receptor agonists, (+)-epibatidine and ABT-594 in models of persistent inflammatory and neuropathic pain".Pain.86(1–2): 113–8.doi:10.1016/s0304-3959(00)00233-5.PMID10779668.S2CID26170267.
  7. ^Sorbera LA, Revel L, Leeson P, Castaner J (2001). "ABT-594".Drugs of the Future.26(10): 927.doi:10.1358/dof.2001.026.10.640317.
  8. ^Lynch JJ, Wade CL, Mikusa JP, Decker MW, Honore P (February 2005). "ABT-594 (a nicotinic acetylcholine agonist): anti-allodynia in a rat chemotherapy-induced pain model".European Journal of Pharmacology.509(1): 43–8.doi:10.1016/j.ejphar.2004.12.034.PMID15713428.
  9. ^Jain KK (January 2004). "Modulators of nicotinic acetylcholine receptors as analgesics".Current Opinion in Investigational Drugs.5(1): 76–81.PMID14983978.
  10. ^Decker MW, Meyer MD, Sullivan JP (October 2001). "The therapeutic potential of nicotinic acetylcholine receptor agonists for pain control".Expert Opinion on Investigational Drugs.10(10): 1819–30.doi:10.1517/13543784.10.10.1819.PMID11772288.S2CID24924290.
  11. ^Meyer MD (1 April 2006). "Neuronal nicotinic acetylcholine receptors as a target for the treatment of neuropathic pain".Drug Development Research.67(4): 355–359.doi:10.1002/ddr.20099.ISSN1098-2299.S2CID84222640.
  12. ^Baraznenok IL, Jonsson E, Claesson A (March 2005). "3-(2,5-Dihydro-1H-pyrrol-2-ylmethoxy)pyridines: synthesis and analgesic activity".Bioorganic & Medicinal Chemistry Letters.15(6): 1637–40.doi:10.1016/j.bmcl.2005.01.058.PMID15745813.
  13. ^Zhang CX, Ge ZM, Cheng TM, Li RT (April 2006). "Synthesis and analgesic activity of secondary amine analogues of pyridylmethylamine and positional isomeric analogues of ABT-594".Bioorganic & Medicinal Chemistry Letters.16(7): 2013–6.doi:10.1016/j.bmcl.2005.12.073.PMID16412637.
  14. ^Bunnelle WH, Daanen JF, Ryther KB, Schrimpf MR, Dart MJ, Gelain A, et al. (July 2007). "Structure-activity studies and analgesic efficacy of N-(3-pyridinyl)-bridged bicyclic diamines, exceptionally potent agonists at nicotinic acetylcholine receptors".Journal of Medicinal Chemistry.50(15): 3627–44.doi:10.1021/jm070018l.PMID17585748.
  15. ^Joshi SK, Mikusa JP, Weaver B, Honore P (February 2008)."Morphine and ABT-594 (a nicotinic acetylcholine agonist) exert centrally mediated antinociception in the rat cyclophosphamide cystitis model of visceral pain".The Journal of Pain.9(2): 146–56.doi:10.1016/j.jpain.2007.09.004.PMID18088559.
  16. ^Lloyd GK, Williams M (2000). "Neuronal Nicotinic Acetylcholine Receptors as Novel Drug Targets".Journal of Pharmacology and Experimental Therapeutics.292(2): 461–467.PMID10640281.
  17. ^Vincler M (October 2005). "Neuronal nicotinic receptors as targets for novel analgesics".Expert Opinion on Investigational Drugs.14(10): 1191–8.doi:10.1517/13543784.14.10.1191.PMID16185161.S2CID20618128.
  18. ^Arneric SP, Holladay M, Williams M (October 2007). "Neuronal nicotinic receptors: a perspective on two decades of drug discovery research".Biochemical Pharmacology.Nicotinic Acetylcholine Receptors as Therapeutic Targets: Emerging Frontiers in Basic Research and Clinical Science.74(8): 1092–101.doi:10.1016/j.bcp.2007.06.033.PMID17662959.
  19. ^Wells GB (May 2008)."Structural answers and persistent questions about how nicotinic receptors work".Frontiers in Bioscience.13(13): 5479–510.doi:10.2741/3094.PMC2430769.PMID18508600.
  20. ^Umana IC, Daniele CA, McGehee DS (Oct 2013)."Neuronal nicotinic receptors as analgesic targets: it's a winding road".Biochem Pharmacol.86(8): 1208–14.doi:10.1016/j.bcp.2013.08.001.PMC4127197.PMID23948066.
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