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Tebanicline
Systematic (IUPAC) name
5-([(2R)-azetidin- 2-yl] methoxy)- 2-chloropyridine
Identifiers
CAS number 198283-73-7
ATC code none
PubChem 3075702
Chemical data
Formula C9H11ClN2O 
Mol. mass 198.649
SMILES eMolecules & PubChem
Therapeutic considerations
Pregnancy cat.  ?
Legal status

Tebanicline (Ebanicline, ABT-594) is a drug developed by Abbott, which acts as a partial agonist at neuronal nicotinic acetylcholine receptors, binding to both the α3β4 and the α4β2 subtypes.[1] It was developed as a less toxic analogue of the potent frog-derived compound epibatidine, which is some 200x stronger than morphine as an analgesic but produces extremely dangerous toxic side effects.[2][3] Like epibatidine, tebanicline showed potent analgesic activity against neuropathic pain in both animal and human trials, but with far less toxicity than its parent compound.[4][5][6][7][8][9]

Tebanicline got as far as Phase II trials in humans,[10] but was dropped from further development due to unacceptable incidence of gastrointestinal side effects.[11] However further research in this area is ongoing,[12][13][14][15] and it is expected that development of new neural nicotinic acetylcholine receptor agonists will be likely to lead to novel analgesics suitable for use in humans within the next few years.[16][17][18][19]

References

  1. ^ Jain, KK (2004). "Modulators of nicotinic acetylcholine receptors as analgesics". Current opinion in investigational drugs (London, England : 2000) 5 (1): 76–81. PMID 14983978.  edit
  2. ^ Bannon, AW; Decker, MW; Holladay, MW; Curzon, P; Donnelly-Roberts, D; Puttfarcken, PS; Bitner, RS; Diaz, A et al. (1998). "Broad-spectrum, non-opioid analgesic activity by selective modulation of neuronal nicotinic acetylcholine receptors". Science (New York, N.Y.) 279 (5347): 77–81. PMID 9417028.  edit
  3. ^ Holladay, M.; Wasicak, J.; Lin, N.; He, Y.; Ryther, K.; Bannon, A.; Buckley, M.; Kim, D. et al. (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): 407–412. doi:10.1021/jm9706224. PMID 9484491.  edit
  4. ^ Donnelly-Roberts, DL; Puttfarcken, PS; Kuntzweiler, TA; Briggs, CA; Anderson, DJ; Campbell, JE; Piattoni-Kaplan, M; Mckenna, DG et al. (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. PMID 9580626.  edit
  5. ^ Bannon, AW; Decker, MW; Curzon, P; Buckley, MJ; Kim, DJ; Radek, RJ; Lynch, JK; Wasicak, JT et al. (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. PMID 9580627.  edit
  6. ^ Decker, MW; Bannon, AW; Buckley, MJ; Kim, DJ; Holladay, MW; Ryther, KB; Lin, NH; Wasicak, JT et al. (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. PMID 9617748.  edit
  7. ^ Kesingland, AC; Gentry, CT; Panesar, MS; Bowes, MA; Vernier, JM; Cube, R; Walker, K; Urban, L (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. PMID 10779668.  edit
  8. ^ Sorbera LA, Revel L, Leeson PA, Castaner J. ABT-594. Drugs Future 2001; 26: 927-934).
  9. ^ Lynch Jj, 3.; Wade, C.; Mikusa, J.; Decker, M.; Honore, P. (2005). "ABT-594 (a nicotinic acetylcholine agonist): anti-allodynia in a rat chemotherapy-induced pain model". European journal of pharmacology 509 (1): 43–48. doi:10.1016/j.ejphar.2004.12.034. PMID 15713428.  edit
  10. ^ Decker, M.; Meyer, M.; Sullivan, J. (2001). "The therapeutic potential of nicotinic acetylcholine receptor agonists for pain control". Expert opinion on investigational drugs 10 (10): 1819–1830. doi:10.1517/13543784.10.10.1819. PMID 11772288.  edit
  11. ^ Meyer MD. Neuronal Nicotinic Acetylcholine Receptors as a Target for the Treatment of Neuropathic Pain. Drug Development Research. 2006; 67: 355-359.
  12. ^ Baraznenok, I.; Jonsson, E.; Claesson, A. (2005). "3-(2,5-Dihydro-1H-pyrrol-2-ylmethoxy)pyridines: synthesis and analgesic activity". Bioorganic & medicinal chemistry letters 15 (6): 1637–1640. doi:10.1016/j.bmcl.2005.01.058. PMID 15745813.  edit
  13. ^ Zhang, C.; Ge, Z.; Cheng, T.; Li, R. (2006). "Synthesis and analgesic activity of secondary amine analogues of pyridylmethylamine and positional isomeric analogues of ABT-594". Bioorganic & medicinal chemistry letters 16 (7): 2013–2016. doi:10.1016/j.bmcl.2005.12.073. PMID 16412637.  edit
  14. ^ Bunnelle, W.; Daanen, J.; Ryther, K.; Schrimpf, M.; Dart, M.; Gelain, A.; Meyer, M.; Frost, J. et al. (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): 3627–3644. doi:10.1021/jm070018l. PMID 17585748.  edit
  15. ^ Joshi, S.; Mikusa, J.; Weaver, B.; Honore, P. (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 : official journal of the American Pain Society 9 (2): 146–156. doi:10.1016/j.jpain.2007.09.004. PMID 18088559.  edit
  16. ^ Lloyd GK, Williams M. Neuronal Nicotinic Acetylcholine Receptors as Novel Drug Targets. Journal of Pharmacology and Experimental Therapeutics. 2000; 292:461-467.
  17. ^ Vincler, M. (2005). "Neuronal nicotinic receptors as targets for novel analgesics". Expert opinion on investigational drugs 14 (10): 1191–1198. doi:10.1517/13543784.14.10.1191. PMID 16185161.  edit
  18. ^ Arneric, S.; Holladay, M.; Williams, M. (2007). "Neuronal nicotinic receptors: a perspective on two decades of drug discovery research". Biochemical pharmacology 74 (8): 1092–1101. doi:10.1016/j.bcp.2007.06.033. PMID 17662959.  edit
  19. ^ Wells, GB (2008). "Structural answers and persistent questions about how nicotinic receptors work". Frontiers in bioscience : a journal and virtual library 13: 5479–510. doi:10.2741/3094. PMID 18508600.  edit
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