테바니클라인

Tebanicline
테바니클라인
Tebanicline.svg
임상자료
ATC 코드
  • 없는
식별자
  • 5-{[(2R)-아제티딘-2-yl]메톡시}-2-클로로피리딘
CAS 번호
펍켐 CID
IUPHAR/BPS
켐스파이더
유니
켐벨
CompTox 대시보드 (EPA)
ECHA InfoCard100.207.679 Edit this at Wikidata
화학 및 물리적 데이터
공식C9H11CLN2O
어금질량198.65 g·190−1
3D 모델(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
  • 키:MKTAGSRKQIEBH-SSDOTTSWSA-N
☒NcheckY (이게 뭐야?) (iii)

테바닉라인(Ebanicline, ABT-594)은 아보트가 개발한 강력한 합성니코틴(비오피오이드) 진통제다. 강력한 독성 다트 개구리 유래 화합물 에피바티딘의 덜 독성이 강한 아날로그로 개발돼 진통제로 모르핀보다 약 200배 강하지만 극도로 위험한 독성 부작용을 일으킨다.[1][2] 에피바티딘과 마찬가지로 테바니클린은 동물 실험과 인간 실험 모두에서 신경성 통증에 대한 강력한 진통 활성을 보였지만 모화합물보다 독성이 훨씬 적었다.[3][4][5][6][7][8] 뉴런니코틴 아세틸콜린 수용체에서 부분작용제 역할을 하며, α3β4와 α4β2 하위유형에 모두 결합한다.[9]

테바니클라인은 인간에서 임상 2상으로 진행되었으나,[10] 위장관 부작용의 용납할 수 없는 발생으로 인해 추가 개발에서 제외되었다.[11] 다만, 이 분야에 대한 추가 연구가 진행 중이며,[12][13][14][15] 니코틴 아세틸콜린 수용체 작용제의 개발이 진행 중이다.[16][17][18][19] 허용할 수 없는 부작용 프로필 때문에 이 등급의 어떤 에이전트도 성공적으로 인체 임상 시험을 완료하지 못했다. 그 지역에 대한 연구가 계속되고 있다.[20]

참조

  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. 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, L.A.; Revel, L.; Leeson, P.; Castañer, 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, Michael D. (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. ^ Umana IC, Daniele CA, McGehee DS (Oct 2013). "Neuronal nicotinic receptors as analgesic targets: it's a winding road". Biochem Pharmacol. 86 (8): 1208–14. doi:10.1016/j.bcp.2013.08.001. PMC 4127197. PMID 23948066.