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Chemical Compound Review

AC1NSJQT     3-[[(2S)-azetidin-2- yl]methoxy]pyridine

Synonyms: CHEMBL59986, SureCN676026, CHEBI:193801, DNC000127, A-85380, ...
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Disease relevance of A-85380

  • In contrast, infusion of A-85380 directly onto the L5 dorsal root ganglion on the affected side resulted in a dose-dependent and marked anti-allodynia (10-20 microg) at doses that had no effect when injected systemically [1].
  • Analogs of A-85380 appear to be the most promising candidates because of their low toxicity and high selectivity for the alpha4beta2 subtype of nAChRs [2].
  • The iodinated analog (S)-5-[123I]iodo-3-(2-azetidinylmethoxy)pyridine of A-85380 is a new potential SPECT tracer specific for the alpha4beta2 subtype nicotinic acetylcholine receptors, which play an important role in neurodegenerative diseases and in tobacco dependence [3].

High impact information on A-85380


Chemical compound and disease context of A-85380

  • Both ABT-594 ((R)-2-chloro-5-(2-azetidinylmethoxy)pyridine) and A-85380 (3-[2(S)-2-azetidinylmethoxy]pyridine), novel nicotinic agonists that possess potent non-opioid analgesic properties, have high affinity for neuronal nicotinic acetylcholine receptors (nAChR) but do not elicit the pronounced toxicity of epibatidine [7].

Biological context of A-85380

  • (+/-)-Epibatidine (EPIB) and A-85380 are nicotinic acetylcholine receptor (nAChR) agonists that bind to the agonist ([3H]cytisine) binding site with 40 to 50 pM affinity but have different affinities in nAChR subtype selective functional receptor assays [8].
  • Nevertheless, A-85380 derivatives still exhibit slow brain kinetics and a moderate signal-to-noise ratio [9].

Anatomical context of A-85380

  • Further, A-85380 can activate (EC50 = 8.9 +/- 1.9 microM) currents through channels formed by injection of the human alpha 7 subunit into Xenopus oocytes, effects that are attenuated by pretreatment with the alpha 7 nAChR antagonist, methyllycaconitine (10 nM) [10].
  • Both i.c.v. infusion and repeated bolus injections into the cerebral aqueduct of an antisense oligonucleotide against the alpha4 subunit significantly attenuated the antinociceptive effects of the nAChR agonist A-85380 in the paw withdrawal test of acute thermal pain [11].
  • Finally, as measured by in vivo microdialysis, levels of 5-HT, but not NE, in the i.t. space of the lumber region of the spinal cord were significantly increased following the systemic administration of A-85380 [12].

Associations of A-85380 with other chemical compounds

  • In radioligand binding studies, A-85380 is shown to be a potent and selective ligand for the human alpha 4 beta 2 nAChR subtype (Ki = 0.05 + 0.01 nM) relative to the human alpha 7 (Ki = 148 +/- 13 nM) and the muscle alpha 1 beta 1 dg subtype expressed in Torpedo electroplax (Ki = 314 +/- 12 nM) [10].
  • The sensitivities of the alpha4beta2 nicotinic acetylcholine receptors to the agonists acetylcholine, 5-I A-85380, and TC-2559 were investigated using the voltage-clamp technique on Xenopus oocytes and using a fluorescent imaging plate reader to measure calcium responses from HEK-293 cells [13].
  • In order to develop PET/SPECT nAChRs ligands for detection of subtypes of nAChRs nicotine analogues, epibatidine and A-85380 compounds have been characterized in vitro and investigated in vivo [14].

Gene context of A-85380

  • The R-enantiomer of A-85380, A-159470, displays little enantioselectivity towards the alpha 4 beta 2 and alpha 1 beta 1 delta gamma subtypes but does not display 12-fold enantioselectivity towards the alpha 7 subtype (Ki = 1275 +/- 199 nM) [10].

Analytical, diagnostic and therapeutic context of A-85380


  1. Peripheral and central sites of action for A-85380 in the spinal nerve ligation model of neuropathic pain. Rueter, L.E., Kohlhaas, K.L., Curzon, P., Surowy, C.S., Meyer, M.D. Pain (2003) [Pubmed]
  2. Development of ligands for in vivo imaging of cerebral nicotinic receptors. Sihver, W., Nordberg, A., Långström, B., Mukhin, A.G., Koren, A.O., Kimes, A.S., London, E.D. Behav. Brain Res. (2000) [Pubmed]
  3. Measurement of plasma metabolites of (S)-5-[123I]iodo-3-(2-azetidinylmethoxy)pyridine (5-IA-85380), a nicotinic acetylcholine receptor imaging agent, in nonhuman primates. Zoghbi, S.S., Tamagnan, G., Baldwin, M.F., Al-Tikriti, M.S., Amici, L., Seibyl, J.P., Innis, R.B. Nucl. Med. Biol. (2001) [Pubmed]
  4. 5-Iodo-A-85380 binds to alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors (nAChRs) as well as alpha4beta2* subtypes. Kulak, J.M., Sum, J., Musachio, J.L., McIntosh, J.M., Quik, M. J. Neurochem. (2002) [Pubmed]
  5. 2-, 5-, and 6-Halo-3-(2(S)-azetidinylmethoxy)pyridines: synthesis, affinity for nicotinic acetylcholine receptors, and molecular modeling. Koren, A.O., Horti, A.G., Mukhin, A.G., Gündisch, D., Kimes, A.S., Dannals, R.F., London, E.D. J. Med. Chem. (1998) [Pubmed]
  6. Effects of alpha 4/beta 2- and alpha 7-nicotine acetylcholine receptor agonists on prepulse inhibition of the acoustic startle response in rats and mice. Schreiber, R., Dalmus, M., De Vry, J. Psychopharmacology (Berl.) (2002) [Pubmed]
  7. Synthesis and evaluation of 6-[(18)F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine as a PET tracer for nicotinic acetylcholine receptors. Ding, Y., Liu, N., Wang, T., Marecek, J., Garza, V., Ojima, I., Fowler, J.S. Nucl. Med. Biol. (2000) [Pubmed]
  8. Differences between the antinociceptive effects of the cholinergic channel activators A-85380 and (+/-)-epibatidine in rats. Curzon, P., Nikkel, A.L., Bannon, A.W., Arneric, S.P., Decker, M.W. J. Pharmacol. Exp. Ther. (1998) [Pubmed]
  9. The quest for Eldorado: development of radioligands for in vivo imaging of nicotinic acetylcholine receptors in human brain. Horti, A.G., Villemagne, V.L. Curr. Pharm. Des. (2006) [Pubmed]
  10. A-85380 [3-(2(S)-azetidinylmethoxy) pyridine]: in vitro pharmacological properties of a novel, high affinity alpha 4 beta 2 nicotinic acetylcholine receptor ligand. Sullivan, J.P., Donnelly-Roberts, D., Briggs, C.A., Anderson, D.J., Gopalakrishnan, M., Piattoni-Kaplan, M., Campbell, J.E., McKenna, D.G., Molinari, E., Hettinger, A.M., Garvey, D.S., Wasicak, J.T., Holladay, M.W., Williams, M., Arneric, S.P. Neuropharmacology (1996) [Pubmed]
  11. Reduced nicotinic receptor-mediated antinociception following in vivo antisense knock-down in rat. Bitner, R.S., Nikkel, A.L., Curzon, P., Donnelly-Roberts, D.L., Puttfarcken, P.S., Namovic, M., Jacobs, I.C., Meyer, M.D., Decker, M.W. Brain Res. (2000) [Pubmed]
  12. Spinal mechanisms underlying A-85380-induced effects on acute thermal pain. Rueter, L.E., Meyer, M.D., Decker, M.W. Brain Res. (2000) [Pubmed]
  13. 5-I A-85380 and TC-2559 differentially activate heterologously expressed alpha4beta2 nicotinic receptors. Zwart, R., Broad, L.M., Xi, Q., Lee, M., Moroni, M., Bermudez, I., Sher, E. Eur. J. Pharmacol. (2006) [Pubmed]
  14. Ligands for in vivo imaging of nicotinic receptor subtypes in Alzheimer brain. Sihver, W., Långström, B., Nordberg, A. Acta Neurol. Scand., Suppl. (2000) [Pubmed]
  15. Measuring nicotinic receptors with characteristics of alpha4beta2, alpha3beta2 and alpha3beta4 subtypes in rat tissues by autoradiography. Perry, D.C., Xiao, Y., Nguyen, H.N., Musachio, J.L., Dávila-García, M.I., Kellar, K.J. J. Neurochem. (2002) [Pubmed]
  16. Synthesis of an I-123 analog of A-85380 and preliminary SPECT imaging of nicotinic receptors in baboon. Musachio, J.L., Villemagne, V.L., Scheffel, U.A., Dannals, R.F., Dogan, A.S., Yokoi, F., Wong, D.F. Nucl. Med. Biol. (1999) [Pubmed]
  17. Mechanism of action of A-85380 in an animal model of depression. Buckley, M.J., Surowy, C., Meyer, M., Curzon, P. Prog. Neuropsychopharmacol. Biol. Psychiatry (2004) [Pubmed]
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