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.
Highlights
Nicotinic acetylcholine receptors belong to the cys-loop superfamily of ligandgated ion channels, which are widely distributed in the central and peripheral nervous systems
The heteromeric α4β2*–nicotinic acetylcholine receptor (nAChR) complexes are the predominant form of nAChRs in the central nervous system (CNS) and have been pursued as drug targets for various CNS disorders including, but not limited to, nicotine addiction, Parkinson's disease, depression, and pain[1]
In this paper we describe the synthesis and biological evaluation of novel hybrid compounds which combine the substituted cyclopropyl or isoxazolyl side chains of our recently identified α4β2-nAChR partial agonists (3 and 4) with N-pyridyldiamines (7 and 8)
Summary
Nicotinic acetylcholine receptors (nAChRs) belong to the cys-loop superfamily of ligandgated ion channels, which are widely distributed in the central and peripheral nervous systems. The best-known drug targeting the α4β2* receptors is the partial agonist varenicline (1)[2], which is considered to be the treatment of choice for long-term smoking cessation. This is consistent with the well-established role of α4β2*-nAChR mediation of the reinforcing properties of nicotine[3, 4]. Of particular interest for the clinical use of varenicline is the observation of improved mood and cognition both in non-depressed and depressed smokers attempting to quit[5] Another α4β2*–nAChR partial agonist, CP-601,297 (2), was recently shown to possess clinical antidepressant efficacy in non-obese subjects[6]. Potent partial agonists of α4β2*-nAChRs that are highly selective over the α3β4* subtypes are expected to exert higher efficacy and likely fewer side effects in rodent behavioral models of mood disorders
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