Wikipedia

Tebanicline

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
Clinical data
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 ☒N
  • Key:MKTAGSRKQIGEBH-SSDOTTSWSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

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

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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

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References

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  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. ↑ Jain KK (January 2004). "Modulators of nicotinic acetylcholine receptors as analgesics". Current Opinion in Investigational Drugs. 5 (1): 76–81. PMID 14983978.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  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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