Enantiopure cyclopropane-bearing pyridyldiazabicyclo[3.3.0]octanes as selective α4β2-nAChR ligands

Oluseye K. Onajole; J. Brek Eaton; Ronald J. Lukas; Dani Brunner; Lucinda Thiede; Barbara J. Caldarone; Alan P. Kozikowski

doi:10.1021/ml500129k

Enantiopure cyclopropane-bearing pyridyldiazabicyclo[3.3.0]octanes as selective α4β2-nAChR ligands

Oluseye K. Onajole, J. Brek Eaton, Ronald J. Lukas, Dani Brunner, Lucinda Thiede, Barbara J. Caldarone, Alan P. Kozikowski

School of Medicine

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

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 α4β2-nicotinic acetylcholine receptor (nAChR) subtype. Structure-activity 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 β2 subunit-containing nAChR subtypes (β2∗-nAChRs) over α4∗-nAChRs compared to the parent compound 4. Compound 15 exhibited subnanomolar binding affinity for α4β2-and α4β2∗-nAChRs with negligible interaction. Functional assays confirm selectivity for α4β2-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.

Original language	English (US)
Pages (from-to)	1196-1201
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	5
Issue number	11
DOIs	https://doi.org/10.1021/ml500129k
State	Published - Nov 13 2014

Keywords

N-pyridyldiazabicyclo[3.3.0]octane
Nicotinic acetylcholine receptor
selective α4β2 partial agonist

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/ml500129k

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title = "Enantiopure cyclopropane-bearing pyridyldiazabicyclo[3.3.0]octanes as selective α4β2-nAChR ligands",

abstract = "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 α4β2-nicotinic acetylcholine receptor (nAChR) subtype. Structure-activity 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 β2 subunit-containing nAChR subtypes (β2∗-nAChRs) over α4∗-nAChRs compared to the parent compound 4. Compound 15 exhibited subnanomolar binding affinity for α4β2-and α4β2∗-nAChRs with negligible interaction. Functional assays confirm selectivity for α4β2-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 = "N-pyridyldiazabicyclo[3.3.0]octane, Nicotinic acetylcholine receptor, selective α4β2 partial agonist",

author = "Onajole, {Oluseye K.} and Eaton, {J. Brek} and Lukas, {Ronald J.} and Dani Brunner and Lucinda Thiede and Caldarone, {Barbara J.} and Kozikowski, {Alan P.}",

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year = "2014",

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doi = "10.1021/ml500129k",

language = "English (US)",

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T1 - Enantiopure cyclopropane-bearing pyridyldiazabicyclo[3.3.0]octanes as selective α4β2-nAChR ligands

AU - Onajole, Oluseye K.

AU - Eaton, J. Brek

AU - Lukas, Ronald J.

AU - Brunner, Dani

AU - Thiede, Lucinda

AU - Caldarone, Barbara J.

AU - Kozikowski, Alan P.

PY - 2014/11/13

Y1 - 2014/11/13

N2 - 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 α4β2-nicotinic acetylcholine receptor (nAChR) subtype. Structure-activity 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 β2 subunit-containing nAChR subtypes (β2∗-nAChRs) over α4∗-nAChRs compared to the parent compound 4. Compound 15 exhibited subnanomolar binding affinity for α4β2-and α4β2∗-nAChRs with negligible interaction. Functional assays confirm selectivity for α4β2-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.

AB - 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 α4β2-nicotinic acetylcholine receptor (nAChR) subtype. Structure-activity 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 β2 subunit-containing nAChR subtypes (β2∗-nAChRs) over α4∗-nAChRs compared to the parent compound 4. Compound 15 exhibited subnanomolar binding affinity for α4β2-and α4β2∗-nAChRs with negligible interaction. Functional assays confirm selectivity for α4β2-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.

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KW - selective α4β2 partial agonist

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Enantiopure cyclopropane-bearing pyridyldiazabicyclo[3.3.0]octanes as selective α4β2-nAChR ligands

Abstract

Keywords

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