Tebanicline Explained

Tebanicline (ebanicline, ABT-594) is a potent synthetic nicotinic (non-opioid) analgesic drug developed by Abbott. It was developed as a less toxic analog of the potent poison dart frog-derived compound epibatidine, which is about 200 times 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 progressed to Phase II clinical 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 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]

Notes and References

  1. Bannon AW, Decker MW, Holladay MW, Curzon P, Donnelly-Roberts D, Puttfarcken PS, Bitner RS, Diaz A, Dickenson AH, Porsolt RD, Williams M, Arneric SP . 6 . Broad-spectrum, non-opioid analgesic activity by selective modulation of neuronal nicotinic acetylcholine receptors . Science . 279 . 5347 . 77–81 . January 1998 . 9417028 . 10.1126/science.279.5347.77 . 1998Sci...279...77B .
  2. Holladay MW, Wasicak JT, Lin NH, He Y, Ryther KB, Bannon AW, Buckley MJ, Kim DJ, Decker MW, Anderson DJ, Campbell JE, Kuntzweiler TA, Donnelly-Roberts DL, Piattoni-Kaplan M, Briggs CA, Williams M, Arneric SP . 6 . 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 . February 1998 . 9484491 . 10.1021/jm9706224 .
  3. Donnelly-Roberts DL, Puttfarcken PS, Kuntzweiler TA, Briggs CA, Anderson DJ, Campbell JE, Piattoni-Kaplan M, McKenna DG, Wasicak JT, Holladay MW, Williams M, Arneric SP . 6 . 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 . May 1998 . 9580626 .
  4. Bannon AW, Decker MW, Curzon P, Buckley MJ, Kim DJ, Radek RJ, Lynch JK, Wasicak JT, Lin NH, Arnold WH, Holladay MW, Williams M, Arneric SP . 6 . 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 . May 1998 . 9580627 .
  5. Decker MW, Bannon AW, Buckley MJ, Kim DJ, Holladay MW, Ryther KB, Lin NH, Wasicak JT, Williams M, Arneric SP . 6 . Antinociceptive effects of the novel neuronal nicotinic acetylcholine receptor agonist, ABT-594, in mice . European Journal of Pharmacology . 346 . 1 . 23–33 . April 1998 . 9617748 . 10.1016/S0014-2999(98)00042-9 .
  6. Kesingland AC, Gentry CT, Panesar MS, Bowes MA, Vernier JM, Cube R, Walker K, Urban L . 6 . 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 . May 2000 . 10779668 . 10.1016/s0304-3959(00)00233-5 . 26170267 .
  7. Sorbera LA, Revel L, Leeson P, Castaner J . ABT-594. Drugs of the Future. 26. 10. 927. 10.1358/dof.2001.026.10.640317. 2001.
  8. Lynch JJ, Wade CL, Mikusa JP, Decker MW, Honore P . ABT-594 (a nicotinic acetylcholine agonist): anti-allodynia in a rat chemotherapy-induced pain model . European Journal of Pharmacology . 509 . 1 . 43–8 . February 2005 . 15713428 . 10.1016/j.ejphar.2004.12.034 .
  9. Jain KK . Modulators of nicotinic acetylcholine receptors as analgesics . Current Opinion in Investigational Drugs . 5 . 1 . 76–81 . January 2004 . 14983978 .
  10. Decker MW, Meyer MD, Sullivan JP . The therapeutic potential of nicotinic acetylcholine receptor agonists for pain control . Expert Opinion on Investigational Drugs . 10 . 10 . 1819–30 . October 2001 . 11772288 . 10.1517/13543784.10.10.1819 . 24924290 .
  11. Meyer MD . Neuronal nicotinic acetylcholine receptors as a target for the treatment of neuropathic pain. Drug Development Research. 1 April 2006. 1098-2299. 355–359. 67. 4. 10.1002/ddr.20099. 84222640.
  12. Baraznenok IL, Jonsson E, Claesson A . 3-(2,5-Dihydro-1H-pyrrol-2-ylmethoxy)pyridines: synthesis and analgesic activity . Bioorganic & Medicinal Chemistry Letters . 15 . 6 . 1637–40 . March 2005 . 15745813 . 10.1016/j.bmcl.2005.01.058 .
  13. Zhang CX, Ge ZM, Cheng TM, Li RT . 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 . April 2006 . 16412637 . 10.1016/j.bmcl.2005.12.073 .
  14. Bunnelle WH, Daanen JF, Ryther KB, Schrimpf MR, Dart MJ, Gelain A, Meyer MD, Frost JM, Anderson DJ, Buckley M, Curzon P, Cao YJ, Puttfarcken P, Searle X, Ji J, Putman CB, Surowy C, Toma L, Barlocco D . 6 . 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 . July 2007 . 17585748 . 10.1021/jm070018l .
  15. Joshi SK, Mikusa JP, Weaver B, Honore P . 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 . February 2008 . 18088559 . 10.1016/j.jpain.2007.09.004 . free .
  16. Lloyd GK, Williams M . 2000 . Neuronal Nicotinic Acetylcholine Receptors as Novel Drug Targets . Journal of Pharmacology and Experimental Therapeutics . 292 . 2. 461–467 . 10640281 .
  17. Vincler M . Neuronal nicotinic receptors as targets for novel analgesics . Expert Opinion on Investigational Drugs . 14 . 10 . 1191–8 . October 2005 . 16185161 . 10.1517/13543784.14.10.1191 . 20618128 .
  18. Arneric SP, Holladay M, Williams M . Neuronal nicotinic receptors: a perspective on two decades of drug discovery research . Biochemical Pharmacology . 74 . 8 . 1092–101 . October 2007 . 17662959 . 10.1016/j.bcp.2007.06.033 . Nicotinic Acetylcholine Receptors as Therapeutic Targets: Emerging Frontiers in Basic Research and Clinical Science .
  19. Wells GB . Structural answers and persistent questions about how nicotinic receptors work . Frontiers in Bioscience . 13 . 13 . 5479–510 . May 2008 . 18508600 . 2430769 . 10.2741/3094 .
  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 . 10.1016/j.bcp.2013.08.001 . 23948066 . 4127197 .

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