Chemistry, pharmacology, and behavioral studies identify chiral cyclopropanes as selective α4β2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile. Part II

Han-Kun Zhang; Li-Fang Yu; J Brek Eaton; Paul Whiteaker; Oluseye K Onajole; Taleen Hanania; Daniela Brunner; Ronald J Lukas; Alan P Kozikowski

doi:10.1021/jm400510u

Chemistry, pharmacology, and behavioral studies identify chiral cyclopropanes as selective α4β2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile. Part II

J Med Chem. 2013 Jul 11;56(13):5495-504. doi: 10.1021/jm400510u. Epub 2013 Jun 26.

Authors

Han-Kun Zhang¹, Li-Fang Yu, J Brek Eaton, Paul Whiteaker, Oluseye K Onajole, Taleen Hanania, Daniela Brunner, Ronald J Lukas, Alan P Kozikowski

Affiliation

¹ Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.

Abstract

A 3-pyridyl ether scaffold bearing a cyclopropane-containing side chain was recently identified in our efforts to create novel antidepressants that act as partial agonists at α4β2-nicotinic acetylcholine receptors. In this study, a systematic structure-activity relationship investigation was carried out on both the azetidine moiety present in compound 3 and its right-hand side chain, thereby discovering a variety of novel nicotinic ligands that retain bioactivity and feature improved chemical stability. The most promising compounds, 24, 26, and 30, demonstrated comparable or enhanced pharmacological profiles compared to the parent compound 4, and the N-methylpyrrolidine analogue 26 also exhibited robust antidepressant-like efficacy in the mouse forced swim test. The favorable ADMET profile and chemical stability of 26 further indicate this compound to be a promising lead as a drug candidate warranting further advancement down the drug discovery pipeline.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antidepressive Agents / chemistry
Antidepressive Agents / pharmacology*
Binding, Competitive
Caco-2 Cells
Cell Line
Cell Line, Tumor
Cyclopropanes / chemistry
Cyclopropanes / metabolism
Cyclopropanes / pharmacology*
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 Enzyme System / metabolism
Drug Stability
Humans
Male
Mice
Mice, Inbred BALB C
Microsomes, Liver / drug effects
Microsomes, Liver / enzymology
Microsomes, Liver / metabolism
Models, Chemical
Molecular Structure
Motor Activity / drug effects
Nicotinic Agonists / chemistry
Nicotinic Agonists / pharmacology*
Radioligand Assay
Rats
Receptors, Nicotinic / metabolism*
Stereoisomerism
Structure-Activity Relationship
Swimming / psychology

Substances

Antidepressive Agents
Cyclopropanes
Cytochrome P-450 Enzyme Inhibitors
Nicotinic Agonists
Receptors, Nicotinic
nicotinic receptor alpha4beta2
Cytochrome P-450 Enzyme System

Abstract

Publication types

MeSH terms

Substances

Grants and funding