Tebanicline

Chemical compound From Wikipedia, the free encyclopedia

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]

ATC code

none

CAS Number

198283-73-7^Y

PubChem CID

3075702

IUPHAR/BPS

3989

Quick facts Clinical data, ATC code ...

Tebanicline
Clinical data

ATC code	none
Identifiers
IUPAC name 5-{[(2R)-Azetidin-2-yl]methoxy}-2-chloropyridine
CAS Number	198283-73-7^Y
PubChem CID	3075702
IUPHAR/BPS	3989
ChemSpider	2334347^N
UNII	9KX8NKV538
ChEBI	CHEBI:234304
ChEMBL	ChEMBL430497^N
CompTox Dashboard (EPA)	DTXSID90173555
ECHA InfoCard	100.207.679
Chemical and physical data
Formula	C₉H₁₁ClN₂O
Molar mass	198.65 g·mol⁻¹
3D model (JSmol)	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^N Key:MKTAGSRKQIGEBH-SSDOTTSWSA-N^N
^NY (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

Goldstein reported a series of agents that are based on a cyclopropane ring.^[21]

References

[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]
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): 2188–2193. doi:10.1016/j.bmcl.2007.12.075. PMID 18262785.

Tebanicline

Analogs

See also

References

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