Enantiopure Cyclopropane-Bearing Pyridyldiazabicyclo[3.3.0]octanes as Selective 伪4尾2-nAChR Ligands

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• 作者：Oluseye K. Onajole ; J. Brek Eaton ; Ronald J. Lukas ; Dani Brunner ; Lucinda Thiede ; Barbara J. Caldarone ; Alan P. Kozikowski
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2014
• 出版时间：November 13, 2014
• 年：2014
• 卷：5
• 期：11
• 页码：1196-1201
• 全文大小：300K
• ISSN：1948-5875

文摘

We report the synthesis and characterization of a series of enantiopure 5-cyclopropane-bearing pyridyldiazabicyclo[3.3.0]octanes that display low nanomolar binding affinities and act as functional agonists at 伪4尾2-nicotinic acetylcholine receptor (nAChR) subtype. Structure鈥揳ctivity relationship studies revealed that incorporation of a cyclopropane-containing side chain at the 5-position of the pyridine ring provides ligands with improved subtype selectivity for nAChR 尾2 subunit-containing nAChR subtypes (尾2*-nAChRs) over 尾4*-nAChRs compared to the parent compound 4. Compound 15 exhibited subnanomolar binding affinity for 伪4尾2- and 伪4尾2*-nAChRs with negligible interaction. Functional assays confirm selectivity for 伪4尾2-nAChRs. Furthermore, using the SmartCube assay system, this ligand showed antidepressant, anxiolytic, and antipsychotic features, while mouse forced-swim assay further confirm the antidepressant-like property of 15.

Keywords:

Nicotinic acetylcholine receptor; selective 伪4尾2 partial agonist; N-pyridyldiazabicyclo[3.3.0]octane