Tebanicline

Drugbox
IUPAC_name = 5-( [(2R)-azetidin-2-yl] methoxy)-2-chloropyridine


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CAS_number= 198283-73-7
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PubChem= 3075702
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C=9 | H=11 | Cl=1 | N=2 | O=1
molecular_weight = 198.649
smiles = C1CN [C@H] 1COC2=CN=C(C=C2)Cl
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Tebanicline (Ebanicline, ABT-594) is a drug developed by Abbott, which acts as a partial agonist at neural nicotinic acetylcholine receptors, binding to both the α3β4 and the α4β2 subtypes. [Jain KK. Modulators of nicotinic acetylcholine receptors as analgesics. "Current Opinion in Investigational Drugs". 2004 Jan;5(1):76-81. PMID 14983978] It was developed as a less toxic analogue of the potent frog-derived compound epibatidine, which is some 200x stronger than morphine as an analgesic but produces extremely dangerous toxic side effects. [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. Broad-spectrum, non-opioid analgesic activity by selective modulation of neuronal nicotinic acetylcholine receptors."Science". 1998 Jan 2;279(5347):77-81. PMID 9417028] [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. 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". 1998 Feb 12;41(4):407-12. PMID 9484491] 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. [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. ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine] : a novel, orally effective analgesic acting via neuronal nicotinic acetylcholine receptors: I. In vitro characterization. "Journal of Pharmacology and Experimental Therapeutics". 1998 May;285(2):777-86. PMID 9580626] [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. ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine] : a novel, orally effective antinociceptive agent acting via neuronal nicotinic acetylcholine receptors: II. In vivo characterization. "Journal of Pharmacology and Experimental Therapeutics". 1998 May;285(2):787-94. PMID 9580627] [Decker MW, Bannon AW, Buckley MJ, Kim DJ, Holladay MW, Ryther KB, Lin NH, Wasicak JT, Williams M, Arneric SP. Antinociceptive effects of the novel neuronal nicotinic acetylcholine receptor agonist, ABT-594, in mice. "European Journal of Pharmacology". 1998 Apr 3;346(1):23-33. PMID 9617748] [Kesingland AC, Gentry CT, Panesar MS, Bowes MA, Vernier JM, Cube R, Walker K, Urban L. Analgesic profile of the nicotinic acetylcholine receptor agonists, (+)-epibatidine and ABT-594 in models of persistent inflammatory and neuropathic pain. "Pain". 2000 May;86(1-2):113-8. PMID 10779668] [Sorbera LA, Revel L, Leeson PA, Castaner J. ABT-594. "Drugs Future" 2001; 26: 927-934).] [Lynch JJ 3rd, 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". 2005 Feb 10;509(1):43-8. PMID 15713428]

Tebanicline got as far as Phase II trials in humans, [Decker MW, Meyer MD, Sullivan JP. The therapeutic potential of nicotinic acetylcholine receptor agonists for pain control. "Expert Opinion on Investigational Drugs". 2001 Oct;10(10):1819-30. PMID 11772288] but was dropped from further development due to unacceptable incidence of gastrointestinal side effects. [Meyer MD. Neuronal Nicotinic Acetylcholine Receptors as a Target for the Treatment of Neuropathic Pain. "Drug Development Research". 2006; 67: 355-359.] However further research in this area is ongoing, [Baraznenok IL, Jonsson E, Claesson A. 3-(2,5-Dihydro-1H-pyrrol-2-ylmethoxy)pyridines: synthesis and analgesic activity. "Bioorganic and Medicinal Chemistry Letters". 2005 Mar 15;15(6):1637-40. PMID 15745813] [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 and Medicinal Chemistry Letters". 2006 Apr 1;16(7):2013-6. PMID 16412637] [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. Structure-activity studies and analgesic efficacy of N-(3-pyridinyl)-bridged bicyclic diamines, exceptionally potent agonists at nicotinic acetylcholine receptors. "Journal of Medicinal Chemistry". 2007 Jul 26;50(15):3627-44. PMID 17585748] [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. "Journal of Pain". 2008 Feb;9(2):146-56. PMID 18088559] and it is expected that development of new neural nicotinic acetylcholine receptor agonists will be likely to lead to novel analgesics suitable for use in humans within the next few years. [Lloyd GK, Williams M. Neuronal Nicotinic Acetylcholine Receptors as Novel Drug Targets. "Journal of Pharmacology and Experimental Therapeutics". 2000; 292:461-467.] [Vincler M. Neuronal nicotinic receptors as targets for novel analgesics. "Expert Opinion on Investigational Drugs". 2005 Oct;14(10):1191-8. PMID 16185161] [Arneric SP, Holladay M, Williams M. Neuronal nicotinic receptors: a perspective on two decades of drug discovery research. "Biochemical Pharmacology". 2007 Oct 15;74(8):1092-101. PMID 17662959]

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