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Chemical Compound Review

Epibatidine     (4S,6S)-6-(6-chloropyridin-3- yl)-7...

Synonyms: CHEBI:474798, LS-22333, PDSP2_000458, C11H13ClN2, AC1L2Y0E, ...
 
 
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Disease relevance of Epibatidine

  • Even though the alpha4beta2 binding affinity of several of the analogues were equal to that of epibatidine, all of the compounds were weak agonists in the antinociceptive, hypothermia, and spontaneous activity test in mice [1].
  • Likewise, spinal administration of epibatidine after the development of hyperalgesia not only significantly attenuated the decrease in PWL, but prevented further increases in knee joint swelling and temperature [2].
  • The effects of epibatidine and nicotine were further investigated in human neuroblastoma SH-SY5Y cells (expressing alpha3, alpha5, beta2, and beta4 nAChR subunits) [3].
  • Thus, the purpose of the present studies was to evaluate whether the neuronal nicotinic receptor agonist epibatidine possesses antihyperalgesic activity in the formalin model of facial pain [4].
  • The toxicity of epibatidine, because of its nonspecificity for both peripheral and central nicotinic receptors, precludes its development as an analgesic [5].
 

Psychiatry related information on Epibatidine

 

High impact information on Epibatidine

  • Analysis of Aplysia AChBP complexes with nicotinic ligands shows that loop C, which does not significantly change conformation upon binding of the antagonist, methyllycaconitine, further opens to accommodate the peptidic antagonist, alpha-conotoxin ImI, but wraps around the agonists lobeline and epibatidine [10].
  • Type 3 nAChRs bind epibatidine with high affinity in equilibrium binding experiments and show that cytisine is as effective as nicotine in electrophysiological experiments; their distribution and persistence in beta2 -/- mice strongly suggest a subunit composition of alpha3 beta4 [11].
  • Type 4 nAChRs bind cytisine and epibatidine with high affinity in equilibrium binding experiments and persist in beta2 -/- mice; cytisine = nicotine in electrophysiological experiments [11].
  • The nicotinic receptor binding the agonist epibatidine (the high affinity receptor subtype, consisting primarily of alpha3 and alpha4, together with beta2 receptor subunits) was significantly reduced by 40-50% in the granule cell, Purkinje and molecular layers in the autistic compared with the normal group (P < 0.05) [12].
  • The effects of nicotine were equal to bFGF and were mimicked by epibatidine and blocked by hexamethonium [13].
 

Chemical compound and disease context of Epibatidine

 

Biological context of Epibatidine

  • The present study examines binding of acetylcholine (ACh) and epibatidine, agonists with opposite selectivity for the two binding sites of mouse muscle AChRs [17].
  • Point mutations reveal that three sequence differences within the gamma104-117/delta106-delta119 region are determinants of epibatidine selectivity: gammaLys104/deltaTyr106, gammaSer111/deltaTyr113, and gammaTyr117/deltaTyr119 [18].
  • The epibatidine-induced up-regulation of nAChR binding sites in SH-SY5Y cells was one-fourth that in M10 cells [3].
  • Complexes formed by alpha and mutant gamma(K34S+F172I) subunits bind epibatidine with increased affinity compared to alphagamma complexes, whereas the kinetics of alpha2betadeltagamma(K34S+F172I) receptors reveal no change in affinity of the low-affinity site, but increased affinity of the high-affinity site [19].
  • Conformationally constrained epibatidine analogues 20a,b and 23a,b were synthesized using a radical cyclization as the key step [20].
 

Anatomical context of Epibatidine

  • Using the high-affinity agonist epibatidine, we found similar differences in receptor number between strains in both in vitro ligand binding experiments with spinal cord membranes and in situ autoradiographic analyses [21].
  • In rat adrenal glands, 5-iodo-A-85380 binds to nAChRs containing alpha3 and beta4 subunits with 1/1000th the affinity of epibatidine, and exhibits 1/60th and 1/190th the affinity of epibatidine at alpha7 and muscle-type nAChRs, respectively [22].
  • Nicotine exhibited a 14 times lower affinity for the nAChRs in SH-SY5Y cells as compared with M10 cells, whereas epibatidine showed similar affinities for the nAChRs expressed in the two cell lines [3].
  • The every tested dose of epibatidine administered into the locus coeruleus also produced freezing behavior immediately after injection, which was relatively short-lived compared to the analgesic effect [23].
  • The present study tested the hypothesis that the serotonergic dorsal raphe nucleus is a site of action of epibatidine [24].
 

Associations of Epibatidine with other chemical compounds

 

Gene context of Epibatidine

 

Analytical, diagnostic and therapeutic context of Epibatidine

  • These epibatidine analogs have been shown previously to possess high binding affinity to alpha4beta2 but not to alpha7 nAChRs and to inhibit nicotine-induced analgesia in behavioral pain tests [31].
  • Ligand binding and immunoprecipitation studies with subunit-specific antibodies showed that the expression of alphaBungarotoxin (alphaBgtx) and high-affinity epibatidine (Epi) receptors is regulated developmentally and increases until postnatal day 21 (P21) [32].
  • Intrathecal injection of epibatidine alone did not alter pain behaviors, compared to vehicle-treated rats [33].
  • The physiological effects of EP on pain-related behaviors and inflammation were tested after administration to the dorsal horn via a microdialysis fiber [2].
  • The frog toxin epibatidine is one of the most powerful ligands of the neuronal nicotinic receptors and derivatives show promising possibilities for labeling in positron emission tomography studies [34].

References

  1. Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 3'-substituted deschloroepibatidine analogues. Novel nicotinic antagonists. Carroll, F.I., Ma, W., Yokota, Y., Lee, J.R., Brieaddy, L.E., Navarro, H.A., Damaj, M.I., Martin, B.R. J. Med. Chem. (2005) [Pubmed]
  2. Nicotinic cholinergic receptors: potential targets for inflammatory pain relief. Lawand, N.B., Lu, Y., Westlund, K.N. Pain (1999) [Pubmed]
  3. Regulation of nicotinic receptor subtypes following chronic nicotinic agonist exposure in M10 and SH-SY5Y neuroblastoma cells. Warpman, U., Friberg, L., Gillespie, A., Hellström-Lindahl, E., Zhang, X., Nordberg, A. J. Neurochem. (1998) [Pubmed]
  4. Antihyperalgesic activity of epibatidine in the formalin model of facial pain. Gilbert, S.D., Clark, T.M., Flores, C.M. Pain (2001) [Pubmed]
  5. Development of muscarinic analgesics derived from epibatidine: role of the M4 receptor subtype. Ellis, J.L., Harman, D., Gonzalez, J., Spera, M.L., Liu, R., Shen, T.Y., Wypij, D.M., Zuo, F. J. Pharmacol. Exp. Ther. (1999) [Pubmed]
  6. Characterization of the electrophysiological, biochemical and behavioral actions of epibatidine. Bonhaus, D.W., Bley, K.R., Broka, C.A., Fontana, D.J., Leung, E., Lewis, R., Shieh, A., Wong, E.H. J. Pharmacol. Exp. Ther. (1995) [Pubmed]
  7. Attentional effects of nicotinic agonists in rats. Hahn, B., Sharples, C.G., Wonnacott, S., Shoaib, M., Stolerman, I.P. Neuropharmacology (2003) [Pubmed]
  8. Human alpha 7 nicotinic acetylcholine receptor responses to novel ligands. Briggs, C.A., McKenna, D.G., Piattoni-Kaplan, M. Neuropharmacology (1995) [Pubmed]
  9. Nicotinic receptor subtypes in human brain ageing, Alzheimer and Lewy body diseases. Perry, E., Martin-Ruiz, C., Lee, M., Griffiths, M., Johnson, M., Piggott, M., Haroutunian, V., Buxbaum, J.D., Nãsland, J., Davis, K., Gotti, C., Clementi, F., Tzartos, S., Cohen, O., Soreq, H., Jaros, E., Perry, R., Ballard, C., McKeith, I., Court, J. Eur. J. Pharmacol. (2000) [Pubmed]
  10. Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations. Hansen, S.B., Sulzenbacher, G., Huxford, T., Marchot, P., Taylor, P., Bourne, Y. EMBO J. (2005) [Pubmed]
  11. Identification of four classes of brain nicotinic receptors using beta2 mutant mice. Zoli, M., Léna, C., Picciotto, M.R., Changeux, J.P. J. Neurosci. (1998) [Pubmed]
  12. Nicotinic receptor abnormalities in the cerebellar cortex in autism. Lee, M., Martin-Ruiz, C., Graham, A., Court, J., Jaros, E., Perry, R., Iversen, P., Bauman, M., Perry, E. Brain (2002) [Pubmed]
  13. Nicotine accelerates angiogenesis and wound healing in genetically diabetic mice. Jacobi, J., Jang, J.J., Sundram, U., Dayoub, H., Fajardo, L.F., Cooke, J.P. Am. J. Pathol. (2002) [Pubmed]
  14. Effects of a novel cholinergic ion channel agonist SIB-1765F on locomotor activity in rats. Menzaghi, F., Whelan, K.T., Risbrough, V.B., Rao, T.S., Lloyd, G.K. J. Pharmacol. Exp. Ther. (1997) [Pubmed]
  15. Synthesis and analgesic activity of hydrochlorides and quaternary ammoniums of epibatidine incorporated with amino acid ester. Dong, J.C., Wang, X., Li, R.T., Zhang, H.M., Cheng, T.M., Li, C.L. Bioorg. Med. Chem. Lett. (2003) [Pubmed]
  16. Neonicotinoid insecticides: molecular features conferring selectivity for insect versus mammalian nicotinic receptors. Tomizawa, M., Lee, D.L., Casida, J.E. J. Agric. Food Chem. (2000) [Pubmed]
  17. Acetylcholine and epibatidine binding to muscle acetylcholine receptors distinguish between concerted and uncoupled models. Prince, R.J., Sine, S.M. J. Biol. Chem. (1999) [Pubmed]
  18. Structural basis for epibatidine selectivity at desensitized nicotinic receptors. Pennington, R.A., Gao, F., Sine, S.M., Prince, R.J. Mol. Pharmacol. (2005) [Pubmed]
  19. Epibatidine activates muscle acetylcholine receptors with unique site selectivity. Prince, R.J., Sine, S.M. Biophys. J. (1998) [Pubmed]
  20. Synthesis, nicotinic acetylcholine receptor binding affinities, and molecular modeling of constrained epibatidine analogues. Wei, Z.L., Petukhov, P.A., Xiao, Y., Tückmantel, W., George, C., Kellar, K.J., Kozikowski, A.P. J. Med. Chem. (2003) [Pubmed]
  21. Spinal nicotinic receptor expression in spontaneously hypertensive rats. Khan, I.M., Youngblood, K.L., Printz, M.P., Yaksh, T.L., Taylor, P. Hypertension (1996) [Pubmed]
  22. 5-Iodo-A-85380, an alpha4beta2 subtype-selective ligand for nicotinic acetylcholine receptors. Mukhin, A.G., Gündisch, D., Horti, A.G., Koren, A.O., Tamagnan, G., Kimes, A.S., Chambers, J., Vaupel, D.B., King, S.L., Picciotto, M.R., Innis, R.B., London, E.D. Mol. Pharmacol. (2000) [Pubmed]
  23. The locus coeruleus nucleus as a site of action of the antinociceptive and behavioral effects of the nicotinic receptor agonist, epibatidine. Cucchiaro, G., Chaijale, N., Commons, K.G. Neuropharmacology (2006) [Pubmed]
  24. The dorsal raphe nucleus as a site of action of the antinociceptive and behavioral effects of the alpha4 nicotinic receptor agonist epibatidine. Cucchiaro, G., Chaijale, N., Commons, K.G. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  25. Methadone increases intracellular calcium in SH-SY5Y and SH-EP1-halpha7 cells by activating neuronal nicotinic acetylcholine receptors. Pakkanen, J.S., Nousiainen, H., Yli-Kauhaluoma, J., Kylänlahti, I., Möykkynen, T., Korpi, E.R., Peng, J.H., Lukas, R.J., Ahtee, L., Tuominen, R.K. J. Neurochem. (2005) [Pubmed]
  26. exo-2-(Pyridazin-4-yl)-7-azabicyclo[2.2.1]heptanes: syntheses and nicotinic acetylcholine receptor agonist activity of potent pyridazine analogues of (+/-)-epibatidine. Che, D., Wegge, T., Stubbs, M.T., Seitz, G., Meier, H., Methfessel, C. J. Med. Chem. (2001) [Pubmed]
  27. A-85380 and epibatidine each interact with disparate spinal nicotinic receptor subtypes to achieve analgesia and nociception. Khan, I.M., Stanislaus, S., Zhang, L., Taylor, P., Yaksh, T.L. J. Pharmacol. Exp. Ther. (2001) [Pubmed]
  28. The nicotinic acetylcholine receptor agonist (+/-)-epibatidine increases FGF-2 mRNA and protein levels in the rat brain. Belluardo, N., Mudò, G., Blum, M., Cheng, Q., Caniglia, G., Dell'Albani, P., Fuxe, K. Brain Res. Mol. Brain Res. (1999) [Pubmed]
  29. Dystrophin stabilizes alpha 3- but not alpha 7-containing nicotinic acetylcholine receptor subtypes at the postsynaptic apparatus in the mouse superior cervical ganglion. Del Signore, A., Gotti, C., De Stefano, M.E., Moretti, M., Paggi, P. Neurobiol. Dis. (2002) [Pubmed]
  30. Effects of repeated anaesthesia on central cholinergic function in the rat cerebral cortex. Hanning, C.D., Blokland, A., Johnson, M., Perry, E.K. European journal of anaesthesiology. (2003) [Pubmed]
  31. 2-Fluoro-3-(4-nitro-phenyl)deschloroepibatidine is a novel potent competitive antagonist of human neuronal alpha4beta2 nAChRs. Abdrakhmanova, G.R., Damaj, M.I., Carroll, F.I., Martin, B.R. Mol. Pharmacol. (2006) [Pubmed]
  32. Nicotinic acetylcholine receptor subtypes expression during rat retina development and their regulation by visual experience. Moretti, M., Vailati, S., Zoli, M., Lippi, G., Riganti, L., Longhi, R., Viegi, A., Clementi, F., Gotti, C. Mol. Pharmacol. (2004) [Pubmed]
  33. The antinociceptive effect of intrathecal administration of epibatidine with clonidine or neostigmine in the formalin test in rats. Hama, A.T., Lloyd, G.K., Menzaghi, F. Pain (2001) [Pubmed]
  34. Neuronal nAChR stereoselectivity to non-natural epibatidine derivatives. Bertrand, S., Patt, J.T., Spang, J.E., Westera, G., Schubiger, P.A., Bertrand, D. FEBS Lett. (1999) [Pubmed]
 
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