Synthesis and biological evaluation of novel hybrids of highly potent and selective α4β2-Nicotinic acetylcholine receptor (nAChR) partial agonists

Han Kun Zhang, J. Brek Eaton, Allison Fedolak, Hendra Gunosewoyo, Oluseye K. Onajole, Dani Brunner, Ronald J. Lukas, Li Fang Yu, Alan P. Kozikowski

Research output: Contribution to journalArticle

Abstract

We previously reported the cyclopropylpyridine and isoxazolylpyridine ether scaffolds to be versatile building blocks for creating potent α4β2 nicotinic acetylcholine receptor (nAChR) partial agonists with excellent selectivity over the α3β4 subtype. In our continued efforts to develop therapeutic nicotinic ligands, seven novel hybrid compounds were rationally designed, synthesized, and evaluated in [3H]epibatidine binding competition studies. Incorporation of a cyclopropane- or isoxazole-containing side chain onto the 5-position of 1-(pyridin-3-yl)-1,4-diazepane or 2-(pyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane led to highly potent and selective α4β2* nAChR partial agonists with Ki values of 0.5–51.4 nM for α4β2 and negligible affinities for α3β4 and α7. Moreover, compounds 21, 25, and 30 maintained the functional profiles (EC50 and IC50 values of 15–50 nM) of the parent azetidine-containing compounds 3 and 4 in the 86Rb+ ion flux assays. In vivo efficacy of the most promising compound 21 was confirmed in the mouse SmartCube® platform and classical forced swim tests, supporting the potential use of α4β2 partial agonists for treatment of depression.

Original languageEnglish (US)
Pages (from-to)689-697
Number of pages9
JournalEuropean Journal of Medicinal Chemistry
Volume124
DOIs
StatePublished - Nov 29 2016
Externally publishedYes

Keywords

  • Antidepressant-like effects
  • Hybrids
  • Partial agonists
  • α4β2-nAChRs

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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  • Cite this

    Zhang, H. K., Eaton, J. B., Fedolak, A., Gunosewoyo, H., Onajole, O. K., Brunner, D., Lukas, R. J., Yu, L. F., & Kozikowski, A. P. (2016). Synthesis and biological evaluation of novel hybrids of highly potent and selective α4β2-Nicotinic acetylcholine receptor (nAChR) partial agonists. European Journal of Medicinal Chemistry, 124, 689-697. https://doi.org/10.1016/j.ejmech.2016.09.016