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Tebanicline

From Wikipedia, the free encyclopedia
Tebanicline
Clinical data
Other namesEbanicline, ABT-594
ATC code
  • none
Identifiers
  • 5-{[(2R)-Azetidin-2-yl]methoxy}-2-chloropyridine
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.207.679 Edit this at Wikidata
Chemical and physical data
FormulaC9H11ClN2O
Molar mass198.65 g·mol−1
3D model (JSmol)
  • C1CN[C@H]1COC2=CN=C(C=C2)Cl
  • 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 X markN
  • Key:MKTAGSRKQIGEBH-SSDOTTSWSA-N X markN
 X markNcheckY (what is this?)  (verify)

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][9] It acts as a partial agonist at neuronal nicotinic acetylcholine receptors, binding to both the α3β4 and the α4β2 subtypes.[10]

Tebanicline progressed to Phase II clinical trials in humans,[11] but was dropped from further development due to unacceptable incidence of gastrointestinal side effects.[12] However, further research in this area is ongoing,[13][14][15][16] and the development of nicotinic acetylcholine receptor agonists is ongoing.[17][18][19][20] No agents from this class have successfully completed human clinical trials due to their unacceptable side effect profiles.

Analogs

[edit]

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 and 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

[edit]

References

[edit]
  1. ↑ Bannon AW, Decker MW, Holladay MW, Curzon P, Donnelly-Roberts D, Puttfarcken PS, et al. (January 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 MW, Wasicak JT, Lin NH, He Y, Ryther KB, Bannon AW, et al. (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): 407–12. doi:10.1021/jm9706224. PMID 9484491.
  3. ↑ Donnelly-Roberts DL, Puttfarcken PS, Kuntzweiler TA, Briggs CA, Anderson DJ, Campbell JE, et al. (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". The Journal of Pharmacology and Experimental Therapeutics. 285 (2): 777–86. PMID 9580626.
  4. ↑ Bannon AW, Decker MW, Curzon P, Buckley MJ, Kim DJ, Radek RJ, et al. (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". The Journal of Pharmacology and Experimental Therapeutics. 285 (2): 787–94. PMID 9580627.
  5. ↑ Decker MW, Bannon AW, Buckley MJ, Kim DJ, Holladay MW, Ryther KB, et al. (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 AC, Gentry CT, Panesar MS, Bowes MA, Vernier JM, Cube R, et al. (May 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. S2CID 26170267.
  7. ↑ Sorbera LA, Revel L, Leeson P, Castaner J (2001). "ABT-594". Drugs of the Future. 26 (10): 927. doi:10.1358/dof.2001.026.10.640317.
  8. ↑ Lynch JJ, Wade CL, Mikusa JP, Decker MW, Honore P (February 2005). "ABT-594 (a nicotinic acetylcholine agonist): anti-allodynia in a rat chemotherapy-induced pain model". European Journal of Pharmacology. 509 (1): 43–8. doi:10.1016/j.ejphar.2004.12.034. PMID 15713428.
  9. ↑ Meyer MD, Anderson DJ, Campbell JE, Carroll S, Marsh KC, Rodrigues AD, Decker MW (September 2000). "Preclinical Pharmacology of ABT-594: A Nicotinic Acetylcholine Receptor Agonist for the Treatment of Pain". CNS Drug Reviews. 6 (3): 183–194. doi:10.1111/j.1527-3458.2000.tb00146.x.
  10. ↑ Jain KK (January 2004). "Modulators of nicotinic acetylcholine receptors as analgesics". Current Opinion in Investigational Drugs. 5 (1): 76–81. PMID 14983978.
  11. ↑ Decker MW, Meyer MD, Sullivan JP (October 2001). "The therapeutic potential of nicotinic acetylcholine receptor agonists for pain control". Expert Opinion on Investigational Drugs. 10 (10): 1819–30. doi:10.1517/13543784.10.10.1819. PMID 11772288. S2CID 24924290.
  12. ↑ Meyer MD (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. S2CID 84222640.
  13. ↑ Baraznenok IL, Jonsson E, Claesson A (March 2005). "3-(2,5-Dihydro-1H-pyrrol-2-ylmethoxy)pyridines: synthesis and analgesic activity". Bioorganic & Medicinal Chemistry Letters. 15 (6): 1637–40. doi:10.1016/j.bmcl.2005.01.058. PMID 15745813.
  14. ↑ Zhang CX, Ge ZM, Cheng TM, Li RT (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): 2013–6. doi:10.1016/j.bmcl.2005.12.073. PMID 16412637.
  15. ↑ Bunnelle WH, Daanen JF, Ryther KB, Schrimpf MR, Dart MJ, Gelain A, et al. (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): 3627–44. doi:10.1021/jm070018l. PMID 17585748.
  16. ↑ Joshi SK, Mikusa JP, Weaver B, Honore P (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): 146–56. doi:10.1016/j.jpain.2007.09.004. PMID 18088559.
  17. ↑ Lloyd GK, Williams M (2000). "Neuronal Nicotinic Acetylcholine Receptors as Novel Drug Targets". Journal of Pharmacology and Experimental Therapeutics. 292 (2): 461–467. PMID 10640281.
  18. ↑ Vincler M (October 2005). "Neuronal nicotinic receptors as targets for novel analgesics". Expert Opinion on Investigational Drugs. 14 (10): 1191–8. doi:10.1517/13543784.14.10.1191. PMID 16185161. S2CID 20618128.
  19. ↑ Arneric SP, Holladay M, Williams M (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): 1092–101. doi:10.1016/j.bcp.2007.06.033. PMID 17662959.
  20. ↑ Wells GB (May 2008). "Structural answers and persistent questions about how nicotinic receptors work". Frontiers in Bioscience. 13 (13): 5479–510. doi:10.2741/3094. PMC 2430769. PMID 18508600.
  21. ↑ Yuan Y, Yu LF, Qiu X, Kozikowski AP, van Breemen RB (January 2013). "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. doi:10.1016/j.jchromb.2012.11.011. PMC 3538945. PMID 23246847.
  22. ↑ Yu LF, Eaton JB, Fedolak A, Zhang HK, Hanania T, Brunner D, Lukas RJ, Kozikowski AP (November 2012). "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. doi:10.1021/jm301177j. PMC 3532055. PMID 23092294.
  23. ↑ Zhang, H.-K., Gunosewoyo, H., Yan, F., Tang, J., Yu, L.-F. (2016). "Development of Antidepressant Drugs Through Targeting α4β2-Nicotinic Acetylcholine Receptors". In Li, M. D. (ed.). Nicotinic Acetylcholine Receptor Technologies. Neuromethods. Vol. 117. Springer. pp. 207–225. doi:10.1007/978-1-4939-3768-4_11. ISBN 978-1-4939-3766-0.
  24. ↑ Freitas K, Carroll FI, Negus SS (February 2016). "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. doi:10.1037/pha0000055. PMC 4821675. PMID 26461167.
  25. ↑ Akinola LS, Bagdas D, Alkhlaif Y, Jackson A, Gurdap CO, Rahimpour E, Carroll FI, Papke RL, Damaj MI (November 2022). "Pharmacological characterization of 5-iodo-A-85380, a β2-selective nicotinic receptor agonist, in mice". J Psychopharmacol. 36 (11): 1280–93. doi:10.1177/02698811221132214. PMC 9817006. PMID 36321267.
  26. ↑ Guandalini L, Dei S, Manetti D, Romanelli MN, Scapecchi S, Teodori E, Varani K (June 2002). "Synthesis and pharmacological evaluation of some (pyridyl)cyclopropylmethyl amines and their methiodides as nicotinic receptor ligands". Farmaco. 57 (6): 487–496. doi:10.1016/s0014-827x(02)01234-x. PMID 12088064.
  27. ↑ Zhang, H.-K., Yu, L.-F., Eaton, J. B., Whiteaker, P., Onajole, O. K., Hanania, T., Brunner, D., Lukas, R. J., Kozikowski, A. P. (11 July 2013). "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. doi:10.1021/jm400510u. PMC 3843973. PMID 23734673.
  28. ↑ Charton Y, Guillonneau C, Lockhart B, Lestage P, Goldstein S (March 2008). "Preparation and affinity profile of novel nicotinic ligands". Bioorganic & Medicinal Chemistry Letters. 18 (6): 2188–93. doi:10.1016/j.bmcl.2007.12.075. PMID 18262785.
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