Referenced in: none

Automatically associated channels: Kir2.3

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

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

Journal, date & volume: J. Med. Chem., 2013 Jul 11 , 56, 5495-504

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23734673

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.