Tebanicline

Tebanicline

Systematic (IUPAC) name
5-([(2R)-Azetidin-2-yl]methoxy)-2-chloropyridine
Identifiers
CAS Number	198283-73-7
ATC code	none
PubChem	CID 3075702
IUPHAR/BPS	3989
ChemSpider	2334347
UNII	9KX8NKV538
ChEMBL	CHEMBL430497
Chemical data
Formula	C9H11ClN2O
Molar mass	198.649
SMILES C1CN[C@H]1COC2=CN=C(C=C2)Cl
InChI 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 Key:MKTAGSRKQIGEBH-SSDOTTSWSA-N
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Tebanicline (Ebanicline, ABT-594) is a potent synthetic nicotinic (non-opioid) analgesic drug developed by Abbott. It was developed as a less toxic analogue of the potent poison dart frog-derived compound epibatidine, which is some 200x stronger than morphine as an analgesic but produces extremely dangerous toxic side effects.^[1][2] 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.^{[3][4][5][6][7][8]}

Tebanicline got as far as Phase II trials in humans,^[9] but was dropped from further development due to unacceptable incidence of gastrointestinal side effects.^[10] However further research in this area is ongoing,^{[11][12][13][14]} 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.^{[15][16][17][18]}

It acts as a partial agonist at neuronal nicotinic acetylcholine receptors, binding to both the α3β4 and the α4β2 subtypes.^[19]

References

1. Bannon, A. W.; Decker, M. W.; Holladay, M. W.; Curzon, P.; Donnelly-Roberts, D.; Puttfarcken, P. S.; Bitner, R. S.; Diaz, A.; Dickenson, A. H.; Porsolt, R. D.; Williams, M.; Arneric, S. P. (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. PMID 9417028.
2. Holladay, M.; Wasicak, J.; Lin, N.; He, Y.; Ryther, K.; Bannon, A.; Buckley, M.; Kim, D.; Decker, M.; Anderson, D. J.; Campbell, J. E.; Kuntzweiler, T. A.; Donnelly-Roberts, D. L.; Piattoni-Kaplan, M.; Briggs, C. A.; Williams, M.; Arneric, S. P. (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.
3. Donnelly-Roberts, D. L.; Puttfarcken, P. S.; Kuntzweiler, T. A.; Briggs, C. A.; Anderson, D. J.; Campbell, J. E.; Piattoni-Kaplan, M.; McKenna, D. G.; Wasicak, J. T.; Holladay, M. W.; Williams, M.; Arneric, S. P. (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): 777–786. PMID 9580626.
4. Bannon, A. W.; Decker, M. W.; Curzon, P.; Buckley, M. J.; Kim, D. J.; Radek, R. J.; Lynch, J. K.; Wasicak, J. T.; Lin, N. H.; Arnold, W. H.; Holladay, M. W.; Williams, M.; Arneric, S. P. (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): 787–794. PMID 9580627.
5. Decker, M. W.; Bannon, A. W.; Buckley, M. J.; Kim, D. J.; Holladay, M. W.; Ryther, K. B.; Lin, N. H.; Wasicak, J. T.; Williams, M.; Arneric, S. P. (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.
6. Kesingland, A. C.; Gentry, C. T.; Panesar, M. S.; Bowes, M. A.; Vernier, J. M.; 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): 113–118. doi:10.1016/S0304-3959(00)00233-5. PMID 10779668.
7. Sorbera, LA; Revel, L; Leeson, PA; Castaner, J (2001). "ABT-594". Drugs Future 26: 927–934. doi:10.1358/dof.2001.026.10.640317.
8. 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.
9. 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.
10. Meyer, MD (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.
11. 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.
12. 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.
13. Bunnelle, W.; Daanen, J.; Ryther, K.; Schrimpf, M.; Dart, M.; Gelain, A.; Meyer, M.; Frost, J.; Anderson, D.; Buckley, M.; Curzon, P.; Cao, Y. J.; Puttfarcken, P.; Searle, X.; Ji, J.; Putman, C. B.; Surowy, C.; Toma, L.; Barlocco, D. (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.
14. 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.
15. Lloyd, GK; Williams, M (2000). "Neuronal Nicotinic Acetylcholine Receptors as Novel Drug Targets". Journal of Pharmacology and Experimental Therapeutics 292: 461–467.
16. 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.
17. 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.
18. Wells, G. B. (2008). "Structural answers and persistent questions about how nicotinic receptors work". Frontiers in Bioscience 13 (13): 5479–5510. doi:10.2741/3094. PMC 2430769. PMID 18508600.
19. Jain, K. K. (2004). "Modulators of nicotinic acetylcholine receptors as analgesics". Current opinion in investigational drugs (London, England : 2000) 5 (1): 76–81. PMID 14983978.