Tebanicline

Tebanicline

Clinical data
ATC code	none
Identifiers
IUPAC name 5-{[(2R)-Azetidin-2-yl]methoxy}-2-chloropyridine
CAS Number	198283-73-7
PubChem (CID)	3075702
IUPHAR/BPS	3989
ChemSpider	2334347
UNII	9KX8NKV538
ChEMBL	CHEMBL430497
ECHA InfoCard	100.207.679
Chemical and physical data
Formula	C9H11ClN2O
Molar mass	198.65 g·mol^−1
3D model (Jmol)	Interactive image
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]} It acts as a partial agonist at neuronal nicotinic acetylcholine receptors, binding to both the α3β4 and the α4β2 subtypes.^[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 was widely expected that development of new neural nicotinic acetylcholine receptor agonists would be likely to lead to novel analgesics suitable for use in humans within the next few years.^{[16][17][18][19]} In practice however, no agents from this class have made it the whole way through human clinical trials due to their unacceptable side effect profile, though they continue to hold theoretical promise and research in the area continues.^[20]

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. (2 January 1998). "Broad-Spectrum, Non-Opioid Analgesic Activity by Selective Modulation of Neuronal Nicotinic Acetylcholine Receptors". Science. 279 (5347): 77–80. doi:10.1126/science.279.5347.77. ISSN 0036-8075. PMID 9417028.
2. Holladay, Mark W.; Wasicak, James T.; Lin, Nan-Horng; He, Yun; Ryther, Keith B.; Bannon, Anthony W.; Buckley, Michael J.; Kim, David J. B.; Decker, Michael W.; Anderson, David J.; Campbell, Jeffrey E.; Kuntzweiler, Theresa A.; Donnelly-Roberts, Diana L.; Piattoni-Kaplan, Marietta; Briggs, Clark A.; Williams, Michael; Arneric, Stephen P. (1 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): 407–412. doi:10.1021/jm9706224. ISSN 0022-2623. PMID 9484491.
3. Donnelly-Roberts, Diana L.; Puttfarcken, Pamela S.; Kuntzweiler, Theresa A.; Briggs, Clark A.; Anderson, David J.; Campbell, Jeffrey E.; Piattoni-Kaplan, Marietta; Mckenna, David G.; Wasicak, James T.; Holladay, Mark W.; Williams, Michael; Arneric, Stephen P. (1 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". Journal of Pharmacology and Experimental Therapeutics. 285 (2): 777–786. ISSN 1521-0103. PMID 9580626.
4. Bannon, Anthony W.; Decker, Michael W.; Curzon, Peter; Buckley, Michael J.; Kim, David J. B.; Radek, Richard J.; Lynch, John K.; Wasicak, James T.; Lin, Nan-Horng; Arnold, William H.; Holladay, Mark W.; Williams, Michael; Arneric, Stephen P. (1 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". Journal of Pharmacology and Experimental Therapeutics. 285 (2): 787–794. ISSN 1521-0103. PMID 9580627.
5. Decker, Michael W; Bannon, Anthony W; Buckley, Michael J; Kim, David J. B; Holladay, Mark W; Ryther, Keith B; Lin, Nan-Horng; Wasicak, James T; Williams, Michael; Arneric, Stephen P (3 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. PMID 9617748.
6. Kesingland, A. C.; Gentry, C. T.; Panesar, M. S.; Bowes, M. A.; Vernier, J.-M; Cube, R.; Walker, K.; Urban, L. "Analgesic profile of the nicotinic acetylcholine receptor agonists, (+)-epibatidine and ABT-594 in models of persistent inflammatory and neuropathic pain". Pain. 86 (1): 113–118. doi:10.1016/s0304-3959(00)00233-5. PMID 10779668.
7. Sorbera, L.A.; Revel, L.; Leeson, P.; Castañer, J. "ABT-594". Drugs of the Future. 26 (10). doi:10.1358/dof.2001.026.10.640317.
8. Lynch III, James J.; Wade, Carrie L.; Mikusa, Joseph P.; Decker, Michael W.; Honore, Prisca (10 February 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. Jain, Kewal K. (1 January 2004). "Modulators of nicotinic acetylcholine receptors as analgesics". Current Opinion in Investigational Drugs (London, England: 2000). 5 (1): 76–81. ISSN 1472-4472. PMID 14983978.
10. Decker, Michael W.; Meyer, Michael D.; Sullivan, James P. (1 October 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. ISSN 1354-3784. PMID 11772288.
11. Meyer, Michael D. (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. ISSN 1098-2299.
12. Baraznenok, Ivan L.; Jonsson, Emma; Claesson, Alf (15 March 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.
13. Zhang, Chuan-Xin; Ge, Ze-Mei; Cheng, Tie-Ming; Li, Run-Tao (1 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): 2013–2016. doi:10.1016/j.bmcl.2005.12.073. PMID 16412637.
14. Bunnelle, William H.; Daanen, Jerome F.; Ryther, Keith B.; Schrimpf, Michael R.; Dart, Michael J.; Gelain, Arianna; Meyer, Michael D.; Frost, Jennifer M.; Anderson, David J.; Buckley, Michael; Curzon, Peter; Cao, Ying-Jun; Puttfarcken, Pamela; Searle, Xenia; Ji, Jianguo; Putman, C. Brent; Surowy, Carol; Toma, Lucio; Barlocco, Daniela (1 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): 3627–3644. doi:10.1021/jm070018l. ISSN 0022-2623. PMID 17585748.
15. Joshi, S. K.; Mikusa, Joe P.; Weaver, Brenda; Honore, Prisca (1 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): 146–156. doi:10.1016/j.jpain.2007.09.004. PMID 18088559.
16. Lloyd, GK; Williams, M (2000). "Neuronal Nicotinic Acetylcholine Receptors as Novel Drug Targets". Journal of Pharmacology and Experimental Therapeutics. 292: 461–467.
17. Vincler, Michelle (1 October 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. ISSN 1354-3784. PMID 16185161.
18. Arneric, Stephen P.; Holladay, Mark; Williams, Michael (15 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): 1092–1101. doi:10.1016/j.bcp.2007.06.033. PMID 17662959.
19. Wells, Gregg B. (1 May 2008). "Structural answers and persistent questions about how nicotinic receptors work". Frontiers in bioscience : a journal and virtual library. 13: 5479–5510. doi:10.2741/3094. ISSN 1093-9946. PMC 2430769. PMID 18508600.
20. Umana IC, Daniele CA, McGehee DS. Neuronal nicotinic receptors as analgesic targets: it's a winding road. Biochem Pharmacol. 2013 Oct 15;86(8):1208-14. doi: 10.1016/j.bcp.2013.08.001 PMID 23948066