Novel bis-, tris-, and tetrakis-tertiary amino analogs as antagonists at neuronal nicotinic receptors that mediate nicotine-evoked dopamine release

Zhenfa Zhang; Guangrong Zheng; Marharyta Pivavarchyk; A. Gabriela Deaciuc; Linda P. Dwoskin; Peter A. Crooks

doi:10.1016/j.bmcl.2010.11.070

Novel bis-, tris-, and tetrakis-tertiary amino analogs as antagonists at neuronal nicotinic receptors that mediate nicotine-evoked dopamine release

Zhenfa Zhang, Guangrong Zheng, Marharyta Pivavarchyk, A. Gabriela Deaciuc, Linda P. Dwoskin, Peter A. Crooks

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

7 Scopus citations

Abstract

A series of tertiary amine analogs derived from lead azaaromatic quaternary ammonium salts has been designed and synthesized. The preliminary structure-activity relationships of these new analogs suggest that such tertiary amine analogs, which potently inhibit nicotine-evoked dopamine release from rat striatum, represent drug-like inhibitors of α6-containing nicotinic acetylcholine receptors. The bis-tertiary amine analog 7 exhibited an IC ₅₀ of 0.95 nM, while the tris-tertiary amine analog 19 had an IC ₅₀ of 0.35 nM at nAChRs mediating nicotine-evoked dopamine release.

Original language	English
Pages (from-to)	88-91
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	1
DOIs	https://doi.org/10.1016/j.bmcl.2010.11.070
State	Published - Jan 1 2011

Bibliographical note

Funding Information:
This work was supported by NIH . (Grant U19DA017548 )

Funding

This work was supported by NIH . (Grant U19DA017548 )

Funders	Funder number
National Institutes of Health (NIH)
National Institute on Drug Abuse	U19DA017548

Keywords

Smoking cessation
Tobacco dependency
nAChR antagonists

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2010.11.070

Cite this

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title = "Novel bis-, tris-, and tetrakis-tertiary amino analogs as antagonists at neuronal nicotinic receptors that mediate nicotine-evoked dopamine release",

abstract = "A series of tertiary amine analogs derived from lead azaaromatic quaternary ammonium salts has been designed and synthesized. The preliminary structure-activity relationships of these new analogs suggest that such tertiary amine analogs, which potently inhibit nicotine-evoked dopamine release from rat striatum, represent drug-like inhibitors of α6-containing nicotinic acetylcholine receptors. The bis-tertiary amine analog 7 exhibited an IC 50 of 0.95 nM, while the tris-tertiary amine analog 19 had an IC 50 of 0.35 nM at nAChRs mediating nicotine-evoked dopamine release.",

keywords = "Smoking cessation, Tobacco dependency, nAChR antagonists",

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note = "Funding Information: This work was supported by NIH . (Grant U19DA017548 )",

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doi = "10.1016/j.bmcl.2010.11.070",

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AU - Zhang, Zhenfa

AU - Zheng, Guangrong

AU - Pivavarchyk, Marharyta

AU - Deaciuc, A. Gabriela

AU - Dwoskin, Linda P.

AU - Crooks, Peter A.

N1 - Funding Information: This work was supported by NIH . (Grant U19DA017548 )

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N2 - A series of tertiary amine analogs derived from lead azaaromatic quaternary ammonium salts has been designed and synthesized. The preliminary structure-activity relationships of these new analogs suggest that such tertiary amine analogs, which potently inhibit nicotine-evoked dopamine release from rat striatum, represent drug-like inhibitors of α6-containing nicotinic acetylcholine receptors. The bis-tertiary amine analog 7 exhibited an IC 50 of 0.95 nM, while the tris-tertiary amine analog 19 had an IC 50 of 0.35 nM at nAChRs mediating nicotine-evoked dopamine release.

AB - A series of tertiary amine analogs derived from lead azaaromatic quaternary ammonium salts has been designed and synthesized. The preliminary structure-activity relationships of these new analogs suggest that such tertiary amine analogs, which potently inhibit nicotine-evoked dopamine release from rat striatum, represent drug-like inhibitors of α6-containing nicotinic acetylcholine receptors. The bis-tertiary amine analog 7 exhibited an IC 50 of 0.95 nM, while the tris-tertiary amine analog 19 had an IC 50 of 0.35 nM at nAChRs mediating nicotine-evoked dopamine release.

KW - Smoking cessation

KW - Tobacco dependency

KW - nAChR antagonists

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Novel bis-, tris-, and tetrakis-tertiary amino analogs as antagonists at neuronal nicotinic receptors that mediate nicotine-evoked dopamine release

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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