Title

Synthesis And Biological Evaluation Of Novel Hybrids Of Highly Potent And Selective α4β2-Nicotinic Acetylcholine Receptor (Nachr) Partial Agonists

Department

neurobiology

Document Type

Article

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 [ 3 H]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 K i 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 (EC 50 and IC 50 values of 15–50 nM) of the parent azetidine-containing compounds 3 and 4 in the 86 Rb + 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.

Publication Date

1-1-2016

Publication Title

European Journal of Medicinal Chemistry

ISSN

02235234

Volume

124

First Page

689

Last Page

697

Digital Object Identifier (DOI)

10.1016/j.ejmech.2016.09.016

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