Bis-azaaromatic quaternary ammonium salts as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release: An investigation of binding conformation

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

doi:10.1016/j.bmcl.2007.10.052

Bis-azaaromatic quaternary ammonium salts as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release: An investigation of binding conformation

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

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

13 Scopus citations

Abstract

A series of conformationally restricted bis-azaaromatic quaternary ammonium salts (3 and 4) have been designed and synthesized in order to investigate the possible binding conformations of N,N′-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB; 2), a compound which potently inhibits neuronal nicotinic acetylcholine receptors (nAChRs) mediating nicotine-evoked dopamine release. The preliminary structure-activity relationships of these new analogues suggest that bPiDDB binds in an extended conformation at the nAChR binding site, and that flexibility of the linker may be important for its high potency in inhibiting nAChRs mediating nicotine-evoked dopamine release.

Original language	English
Pages (from-to)	6734-6738
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	17
Issue number	24
DOIs	https://doi.org/10.1016/j.bmcl.2007.10.052
State	Published - Dec 15 2007

Bibliographical note

Funding Information:
This research was supported by NIH Grant U19 DA17548.

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.2007.10.052

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title = "Bis-azaaromatic quaternary ammonium salts as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release: An investigation of binding conformation",

abstract = "A series of conformationally restricted bis-azaaromatic quaternary ammonium salts (3 and 4) have been designed and synthesized in order to investigate the possible binding conformations of N,N′-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB; 2), a compound which potently inhibits neuronal nicotinic acetylcholine receptors (nAChRs) mediating nicotine-evoked dopamine release. The preliminary structure-activity relationships of these new analogues suggest that bPiDDB binds in an extended conformation at the nAChR binding site, and that flexibility of the linker may be important for its high potency in inhibiting nAChRs mediating nicotine-evoked dopamine release.",

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

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

note = "Funding Information: This research was supported by NIH Grant U19 DA17548. ",

year = "2007",

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day = "15",

doi = "10.1016/j.bmcl.2007.10.052",

language = "English",

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Bis-azaaromatic quaternary ammonium salts as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release: An investigation of binding conformation. / Zheng, Guangrong; Zhang, Zhenfa; Pivavarchyk, Marharyta et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 17, No. 24, 15.12.2007, p. 6734-6738.

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

TY - JOUR

T1 - Bis-azaaromatic quaternary ammonium salts as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release

T2 - An investigation of binding conformation

AU - Zheng, Guangrong

AU - Zhang, Zhenfa

AU - Pivavarchyk, Marharyta

AU - Deaciuc, Agripina G.

AU - Dwoskin, Linda P.

AU - Crooks, Peter A.

N1 - Funding Information: This research was supported by NIH Grant U19 DA17548.

PY - 2007/12/15

Y1 - 2007/12/15

N2 - A series of conformationally restricted bis-azaaromatic quaternary ammonium salts (3 and 4) have been designed and synthesized in order to investigate the possible binding conformations of N,N′-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB; 2), a compound which potently inhibits neuronal nicotinic acetylcholine receptors (nAChRs) mediating nicotine-evoked dopamine release. The preliminary structure-activity relationships of these new analogues suggest that bPiDDB binds in an extended conformation at the nAChR binding site, and that flexibility of the linker may be important for its high potency in inhibiting nAChRs mediating nicotine-evoked dopamine release.

AB - A series of conformationally restricted bis-azaaromatic quaternary ammonium salts (3 and 4) have been designed and synthesized in order to investigate the possible binding conformations of N,N′-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB; 2), a compound which potently inhibits neuronal nicotinic acetylcholine receptors (nAChRs) mediating nicotine-evoked dopamine release. The preliminary structure-activity relationships of these new analogues suggest that bPiDDB binds in an extended conformation at the nAChR binding site, and that flexibility of the linker may be important for its high potency in inhibiting nAChRs mediating nicotine-evoked dopamine release.

KW - Dopamine release

KW - Nicotine addiction

KW - Nicotinic acetylcholine receptor

KW - Quaternary ammonium

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JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 24

ER -

Bis-azaaromatic quaternary ammonium salts as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release: An investigation of binding conformation

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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