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

doi:10.1016/j.ejmech.2016.09.016

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

Eur J Med Chem. 2016 Nov 29:124:689-697. doi: 10.1016/j.ejmech.2016.09.016. Epub 2016 Sep 9.

Authors

Han-Kun Zhang¹, J Brek Eaton², Allison Fedolak³, Hendra Gunosewoyo⁴, Oluseye K Onajole⁴, Dani Brunner³, Ronald J Lukas², Li-Fang Yu⁵, Alan P Kozikowski⁶

Affiliations

¹ Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, United States; Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
² Division of Neurobiology, Barrow Neurological Institute, 350 West Thomas Road, Phoenix, AZ 85013, United States.
³ PsychoGenics, Inc., 765 Old Saw Mill River Road, Tarrytown, NY 10591, United States.
⁴ Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, United States.
⁵ Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, United States; Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China. Electronic address: lfyu@sat.ecnu.edu.cn.
⁶ Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, United States. Electronic address: kozikowa@uic.edu.

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 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 (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.

Keywords: Antidepressant-like effects; Hybrids; Partial agonists; α4β2-nAChRs.

MeSH terms

Animals
Behavior / drug effects
Depression / drug therapy
Inhibitory Concentration 50
Male
Mice
Mice, Inbred C57BL
Molecular Structure
Nicotinic Agonists / chemical synthesis*
Nicotinic Agonists / chemistry
Nicotinic Agonists / pharmacology*
Nicotinic Agonists / therapeutic use
Receptors, Nicotinic / chemistry
Receptors, Nicotinic / metabolism
Swimming
Varenicline / chemistry
Varenicline / pharmacology

Substances

Nicotinic Agonists
Receptors, Nicotinic
nicotinic receptor alpha4beta2
Varenicline

Grants and funding

U19 MH085193/MH/NIMH NIH HHS/United States