Tetrakis-azaaromatic quaternary ammonium salts: Novel subtype-selective 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.2008.09.084

Tetrakis-azaaromatic quaternary ammonium salts: Novel subtype-selective 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

13 Scopus citations

Abstract

A series of tetrakis-azaaromatic quaternary ammonium salts was synthesized to identify compounds with higher affinity and selectivity as antagonists at neuronal nicotinic receptor subtypes (nAChR) that mediate nicotine-evoked DA release. A high hit rate was achieved in identifying potent analogs that inhibit these nAChRs. Three tetrakis analogs, 11j, 11f, and 11g, were identified as potent (IC₅₀ = 3, 28 and 56 nM, respectively) antagonists at these receptors. These compounds represent a novel structural class of nicotinic receptor antagonists.

Original language	English
Pages (from-to)	5753-5757
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	21
DOIs	https://doi.org/10.1016/j.bmcl.2008.09.084
State	Published - Nov 1 2008

Bibliographical note

Funding Information:
This research was supported by NIH Grant U19DA017548.

Funding

This research was supported by NIH Grant U19DA017548.

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

Keywords

Dopamine release
Nicotine addiction
Nicotinic acetylcholine receptor
Quaternary ammonium

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.2008.09.084

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title = "Tetrakis-azaaromatic quaternary ammonium salts: Novel subtype-selective antagonists at neuronal nicotinic receptors that mediate nicotine-evoked dopamine release",

abstract = "A series of tetrakis-azaaromatic quaternary ammonium salts was synthesized to identify compounds with higher affinity and selectivity as antagonists at neuronal nicotinic receptor subtypes (nAChR) that mediate nicotine-evoked DA release. A high hit rate was achieved in identifying potent analogs that inhibit these nAChRs. Three tetrakis analogs, 11j, 11f, and 11g, were identified as potent (IC50 = 3, 28 and 56 nM, respectively) antagonists at these receptors. These compounds represent a novel structural class of nicotinic receptor antagonists.",

keywords = "Dopamine release, Nicotine addiction, Nicotinic acetylcholine receptor, Quaternary ammonium",

author = "Zhenfa Zhang and Guangrong Zheng and Marharyta Pivavarchyk and Deaciuc, \{A. Gabriela\} and Dwoskin, \{Linda P.\} and Crooks, \{Peter A.\}",

note = "Funding Information: This research was supported by NIH Grant U19DA017548.",

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doi = "10.1016/j.bmcl.2008.09.084",

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Tetrakis-azaaromatic quaternary ammonium salts: Novel subtype-selective antagonists at neuronal nicotinic receptors that mediate nicotine-evoked dopamine release. / Zhang, Zhenfa; Zheng, Guangrong; Pivavarchyk, Marharyta et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 18, No. 21, 01.11.2008, p. 5753-5757.

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

TY - JOUR

T1 - Tetrakis-azaaromatic quaternary ammonium salts

T2 - Novel subtype-selective antagonists at neuronal nicotinic receptors that mediate nicotine-evoked dopamine release

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 research was supported by NIH Grant U19DA017548.

PY - 2008/11/1

Y1 - 2008/11/1

N2 - A series of tetrakis-azaaromatic quaternary ammonium salts was synthesized to identify compounds with higher affinity and selectivity as antagonists at neuronal nicotinic receptor subtypes (nAChR) that mediate nicotine-evoked DA release. A high hit rate was achieved in identifying potent analogs that inhibit these nAChRs. Three tetrakis analogs, 11j, 11f, and 11g, were identified as potent (IC50 = 3, 28 and 56 nM, respectively) antagonists at these receptors. These compounds represent a novel structural class of nicotinic receptor antagonists.

AB - A series of tetrakis-azaaromatic quaternary ammonium salts was synthesized to identify compounds with higher affinity and selectivity as antagonists at neuronal nicotinic receptor subtypes (nAChR) that mediate nicotine-evoked DA release. A high hit rate was achieved in identifying potent analogs that inhibit these nAChRs. Three tetrakis analogs, 11j, 11f, and 11g, were identified as potent (IC50 = 3, 28 and 56 nM, respectively) antagonists at these receptors. These compounds represent a novel structural class of nicotinic receptor antagonists.

KW - Dopamine release

KW - Nicotine addiction

KW - Nicotinic acetylcholine receptor

KW - Quaternary ammonium

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JO - Bioorganic and Medicinal Chemistry Letters

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ER -

Tetrakis-azaaromatic quaternary ammonium salts: Novel subtype-selective antagonists at neuronal nicotinic receptors that mediate nicotine-evoked dopamine release

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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