Chemistry:Tebanicline

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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 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.

CNS Rev:[20]

Analogs

Alan Kozikowski directed research that resulted in such compounds as Sazetidine A (Saz-A) & LF-3-88.[21][22][23] More recently, an additional codename was identified that has been called VMY-2-95 [1434047-61-6].

Niodene & Nifene are the names of two pyridyl ethers that were recently discovered. Niodene is chemically similar to an agent that was explored by Frank Ivy Carroll at RTI called 5-iodo-A-85380 [213550-82-4] .[24][25] It is credit-worthy in making the observation that in the case of nicotine, the azetidine is the optimal ring size and not the natural pyrrolidine.[26] It was reasoned that because of the increased conformational rigidity of the azetidine ring relative to the pyrrolidine, a secondary amine can be well-tolerated. Although this discovery was considered important, it was further discovered that dimerization of the azetidine ring is possible.[27] This prompted a move away from the azetidine rings back to the more conventional N-methyl-pyrrolidines.

Goldstein reported a series of agents that are based on a cyclopropane ring.[28]

See also


References

  1. ↑ "Broad-spectrum, non-opioid analgesic activity by selective modulation of neuronal nicotinic acetylcholine receptors". Science 279 (5347): 77–81. January 1998. doi:10.1126/science.279.5347.77. PMID 9417028. Bibcode: 1998Sci...279...77B. 
  2. ↑ "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. doi:10.1021/jm9706224. PMID 9484491. 
  3. ↑ "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. PMID 9580626. http://jpet.aspetjournals.org/content/285/2/777.long. 
  4. ↑ "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. PMID 9580627. http://jpet.aspetjournals.org/content/285/2/787.long. 
  5. ↑ "Antinociceptive effects of the novel neuronal nicotinic acetylcholine receptor agonist, ABT-594, in mice". European Journal of Pharmacology 346 (1): 23–33. April 1998. doi:10.1016/S0014-2999(98)00042-9. PMID 9617748. 
  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. doi:10.1016/s0304-3959(00)00233-5. PMID 10779668. 
  7. ↑ "ABT-594". Drugs of the Future 26 (10): 927. 2001. doi:10.1358/dof.2001.026.10.640317. 
  8. ↑ "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. doi:10.1016/j.ejphar.2004.12.034. PMID 15713428. 
  9. ↑ "Modulators of nicotinic acetylcholine receptors as analgesics". Current Opinion in Investigational Drugs 5 (1): 76–81. January 2004. PMID 14983978. 
  10. ↑ "The therapeutic potential of nicotinic acetylcholine receptor agonists for pain control". Expert Opinion on Investigational Drugs 10 (10): 1819–30. October 2001. doi:10.1517/13543784.10.10.1819. PMID 11772288. 
  11. ↑ "Neuronal nicotinic acetylcholine receptors as a target for the treatment of neuropathic pain". Drug Development Research 67 (4): 355–359. 1 April 2006. doi:10.1002/ddr.20099. ISSN 1098-2299. 
  12. ↑ "3-(2,5-Dihydro-1H-pyrrol-2-ylmethoxy)pyridines: synthesis and analgesic activity". Bioorganic & Medicinal Chemistry Letters 15 (6): 1637–40. March 2005. doi:10.1016/j.bmcl.2005.01.058. PMID 15745813. 
  13. ↑ "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. doi:10.1016/j.bmcl.2005.12.073. PMID 16412637. 
  14. ↑ "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. doi:10.1021/jm070018l. PMID 17585748. 
  15. ↑ "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. doi:10.1016/j.jpain.2007.09.004. PMID 18088559. 
  16. ↑ "Neuronal Nicotinic Acetylcholine Receptors as Novel Drug Targets". Journal of Pharmacology and Experimental Therapeutics 292 (2): 461–467. 2000. PMID 10640281. 
  17. ↑ "Neuronal nicotinic receptors as targets for novel analgesics". Expert Opinion on Investigational Drugs 14 (10): 1191–8. October 2005. doi:10.1517/13543784.14.10.1191. PMID 16185161. 
  18. ↑ "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. October 2007. doi:10.1016/j.bcp.2007.06.033. PMID 17662959. 
  19. ↑ "Structural answers and persistent questions about how nicotinic receptors work". Frontiers in Bioscience 13 (13): 5479–510. May 2008. doi:10.2741/3094. PMID 18508600. 
  20. ↑ "Preclinical Pharmacology of ABT‐594: A Nicotinic Acetylcholine Receptor Agonist for the Treatment of Pain". CNS Drug Reviews 6 (3): 183–194. September 2000. doi:10.1111/j.1527-3458.2000.tb00146.x. 
  21. ↑ "Pharmacokinetics and brain penetration of LF-3-88, (2-[5-[5-(2(S)-azetidinylmethoxyl)-3-pyridyl-3-isoxazolyl]ethanol), a selective α4β2-nAChR partial agonist and promising antidepressant"]. Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences 912: 38–42. January 2013. doi:10.1016/j.jchromb.2012.11.011. PMID 23246847. 
  22. ↑ "Discovery of highly potent and selective α4β2-nicotinic acetylcholine receptor (nAChR) partial agonists containing an isoxazolylpyridine ether scaffold that demonstrate antidepressant-like activity. Part II". Journal of Medicinal Chemistry 55 (22): 9998–10009. November 2012. doi:10.1021/jm301177j. PMID 23092294. 
  23. ↑ "Development of Antidepressant Drugs Through Targeting α4β2-Nicotinic Acetylcholine Receptors". Nicotinic Acetylcholine Receptor Technologies. Neuromethods. 117. Springer. 2016. pp. 207–225. doi:10.1007/978-1-4939-3768-4_11. ISBN 978-1-4939-3766-0. http://link.springer.com/10.1007/978-1-4939-3768-4_11. 
  24. ↑ "Comparison of effects produced by nicotine and the α4β2-selective agonist 5-I-A-85380 on intracranial self-stimulation in rats". Exp Clin Psychopharmacol 24 (1): 65–75. February 2016. doi:10.1037/pha0000055. PMID 26461167. 
  25. ↑ "Pharmacological characterization of 5-iodo-A-85380, a β2-selective nicotinic receptor agonist, in mice". J Psychopharmacol 36 (11): 1280–93. November 2022. doi:10.1177/02698811221132214. PMID 36321267. 
  26. ↑ "Synthesis and pharmacological evaluation of some (pyridyl)cyclopropylmethyl amines and their methiodides as nicotinic receptor ligands". Farmaco 57 (6): 487–496. June 2002. doi:10.1016/s0014-827x(02)01234-x. PMID 12088064. 
  27. ↑ "Chemistry, Pharmacology, and Behavioral Studies Identify Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile. Part II". Journal of Medicinal Chemistry 56 (13): 5495–5504. 11 July 2013. doi:10.1021/jm400510u. PMID 23734673. 
  28. ↑ "Preparation and affinity profile of novel nicotinic ligands". Bioorganic & Medicinal Chemistry Letters 18 (6): 2188–93. March 2008. doi:10.1016/j.bmcl.2007.12.075. PMID 18262785. 



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