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2-, 5-, and 6-Halo-3-(2(S)-azetidinylmethoxy)pyridines: synthesis, affinity for nicotinic acetylcholine receptors, and molecular modeling.

Publication ,  Journal Article
Koren, AO; Horti, AG; Mukhin, AG; Gündisch, D; Kimes, AS; Dannals, RF; London, ED
Published in: Journal of Medicinal Chemistry
September 1998

3-(2(S)-Azetidinylmethoxy)pyridine (A-85380) has been identified recently as a ligand with high affinity for nicotinic acetylcholine receptors (nAChRs). Here we report the synthesis and in vitro nAChR binding of a series of 10 pyridine-modified analogues of A-85380. The novel compounds feature a halogen substituent at position 2, 5, or 6 of the 3-pyridyl fragment. Those with the substituents at position 5 or 6, as well as the 2-fluoro analogue, possess subnanomolar affinity for nAChRs in membranes from rat brain. For these ligands, Ki values range from 11 to 210 pM, as measured by competition with (+/-)-[3H]epibatidine. In contrast, 2-chloro, 2-bromo, and 2-iodo analogues exhibit substantially lower affinity. AM1 quantum chemical calculations demonstrate that the bulky substituents at position 2 cause notable changes in the molecular geometry. The high-affinity members of the series and (+)-epibatidine display a tight fit superposition of low-energy stable conformers. The new ligands with high affinity for nAChRs may be of interest as pharmacological probes, potential medications, and candidates for developing radiohalogenated tracers to study nAChRs.

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Published In

Journal of Medicinal Chemistry

DOI

EISSN

1520-4804

ISSN

0022-2623

Publication Date

September 1998

Volume

41

Issue

19

Start / End Page

3690 / 3698

Related Subject Headings

  • Structure-Activity Relationship
  • Receptors, Nicotinic
  • Rats, Inbred F344
  • Rats
  • Pyridines
  • Prosencephalon
  • Nicotinic Agonists
  • Models, Molecular
  • Medicinal & Biomolecular Chemistry
  • Male
 

Citation

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Koren, A. O., Horti, A. G., Mukhin, A. G., Gündisch, D., Kimes, A. S., Dannals, R. F., & London, E. D. (1998). 2-, 5-, and 6-Halo-3-(2(S)-azetidinylmethoxy)pyridines: synthesis, affinity for nicotinic acetylcholine receptors, and molecular modeling. Journal of Medicinal Chemistry, 41(19), 3690–3698. https://doi.org/10.1021/jm980170a
Koren, A. O., A. G. Horti, A. G. Mukhin, D. Gündisch, A. S. Kimes, R. F. Dannals, and E. D. London. “2-, 5-, and 6-Halo-3-(2(S)-azetidinylmethoxy)pyridines: synthesis, affinity for nicotinic acetylcholine receptors, and molecular modeling.Journal of Medicinal Chemistry 41, no. 19 (September 1998): 3690–98. https://doi.org/10.1021/jm980170a.
Koren AO, Horti AG, Mukhin AG, Gündisch D, Kimes AS, Dannals RF, et al. 2-, 5-, and 6-Halo-3-(2(S)-azetidinylmethoxy)pyridines: synthesis, affinity for nicotinic acetylcholine receptors, and molecular modeling. Journal of Medicinal Chemistry. 1998 Sep;41(19):3690–8.
Koren, A. O., et al. “2-, 5-, and 6-Halo-3-(2(S)-azetidinylmethoxy)pyridines: synthesis, affinity for nicotinic acetylcholine receptors, and molecular modeling.Journal of Medicinal Chemistry, vol. 41, no. 19, Sept. 1998, pp. 3690–98. Epmc, doi:10.1021/jm980170a.
Koren AO, Horti AG, Mukhin AG, Gündisch D, Kimes AS, Dannals RF, London ED. 2-, 5-, and 6-Halo-3-(2(S)-azetidinylmethoxy)pyridines: synthesis, affinity for nicotinic acetylcholine receptors, and molecular modeling. Journal of Medicinal Chemistry. 1998 Sep;41(19):3690–3698.
Journal cover image

Published In

Journal of Medicinal Chemistry

DOI

EISSN

1520-4804

ISSN

0022-2623

Publication Date

September 1998

Volume

41

Issue

19

Start / End Page

3690 / 3698

Related Subject Headings

  • Structure-Activity Relationship
  • Receptors, Nicotinic
  • Rats, Inbred F344
  • Rats
  • Pyridines
  • Prosencephalon
  • Nicotinic Agonists
  • Models, Molecular
  • Medicinal & Biomolecular Chemistry
  • Male