QSAR modeling of mono- and bis-quaternary ammonium salts that act as antagonists at neuronal nicotinic acetylcholine receptors mediating dopamine release

Zheng, Fang; Bayram, Ersin; Sumithran, Sangeetha P.; Ayers, Joshua T.; Zhan, Chang‐Guo; Schmitt, Jens; Dwoskin, Linda P.; Crooks, Peter A.

doi:10.1016/j.bmc.2005.12.036

Cited by 52 publications

(32 citation statements)

References 35 publications

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“…Based on a previously described procedure [37,38], the relative contributions of the four descriptors to the present model were determined and are plotted in Figure 4 The first important descriptor is the 1-order complementary information content CIC1, which explains 36.8% contribution of the total and correlates relatively high (R = 0.760) with the target experimental K salt values. The descriptor CIC1 [31] is defined by Eq.…”

Section: T a B L Ementioning

confidence: 99%

A simple 2D-QSPR model for the prediction of Setschenow constants of organic compounds

Fan

2016

Maced. J. Chem. Chem. Eng.

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A quantitative structure-property relationship (QSPR) analysis of the Setschenow constants (K salt ) of organic compounds in a sodium chloride solution was carried out using only two-dimensional (2D) descriptors as input parameters. The whole set of 101 compounds was split into a training set of 71 compounds and a validation set of 30 compounds by means of the Kennard and Stones algorithm. A general four-parameter equation, with correlation coefficient (R) of 0.887 and standard error of estimation (s) of 0.031, was obtained by stepwise multilinear regression analysis (MLRA) on the training set. The reliability and robustness of the present model was verified with leave-one-out cross-validation, randomization tests, and the external validation set. All of the descriptors contained in this model are calculated directly from the molecular 2D structures; thus, this model can be used to easily predict the K salt of other compounds not involved in the present dataset.Keywords: QSPR; Setschenow constants; 2D descriptor; multilinear regression analysis ЕДНОСТАВЕН 2D-QSPR-МОДЕЛ ЗА ПРЕДВИДУВАЊЕ НА КОНСТАНТИТЕ НА SETSCHENOW ЗА ОРГАНСКИТЕ СОЕДИНЕНИЈААнализата на квантитативната зависност на структурата и својствата (QSPR) на константите на Setschenow (K salt ) на органските соединенија во раствор од натриум хлорид е извршена користејќи само дводимензионални (2D) дескриптори како влезни параметри. Целото множество од 101 соединение беше поделено во множество за подготовка од 71 соединение и множество за валидација од 30 соединенија според алгоритамот на Kennard и Stones. Од множеството за подготовка со мултилинеарна регресиона анализа MLRA е добиена општа четирипараметарска равенка со коефициент на корелација R = 0,887 и стандардна грешка на процената s = 0,031. Веродостојноста и робусноста на овој модел беше верифицирана со повеќе тестови: вкрстена валидација со испуштање на еден параметар, тест на рандомизација, како и екстерно множество за валидација. Сите дескриптори содржат модел што се пресметува директно од молекулските 2D-структури, и така овој модел може да се користи за едноставно предвидување на K salt на други соединенија што не се вклучени во ова множество на податоци.

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Section: T a B L Ementioning

confidence: 99%

A simple 2D-QSPR model for the prediction of Setschenow constants of organic compounds

Fan

2016

Maced. J. Chem. Chem. Eng.

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“…These results with the nicotinium analogues are consistent with our previous results with mono-nicotinium and bis-nicotinium analogues. 19,30,34 Several analogues, i.e., 3g, 3i, 3j, and 4i, displayed some potency at α7* nAChRs. Notably, all of these four analogues bear bulky, more hydrophobic cationic head groups.…”

Section: Nih Public Accessmentioning

confidence: 99%

“…Previous studies from our laboratories have identified N,N '-dodecane-1,12-diyl-bis-3picolinium dibromide (bPiDDB; 1; Figure 1) as a potent inhibitor (IC 50 = 5 nM) of nAChRs mediating nicotine-evoked [ 3 H]DA release from superfused rat striatal slices. 18,19 In vivo microdialysis studies also demonstrated that pretreatment with bPiDDB dose-dependently reduced nicotine evoked extracellular DA release in rat nucleus accumbens. 20 Moreover, behavioral studies in rats showed that bPiDDB dose-dependently decreased intravenous nicotine self-administration, but not sucrose-maintained responding, suggesting a specific inhibition of nicotine reward.…”

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confidence: 94%

tris-Azaaromatic quaternary ammonium salts: Novel templates as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release

Zheng

Sumithran

Deaciuc

et al. 2007

Bioorganic & Medicinal Chemistry Letters

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A series of tris-azaaromatic quaternary ammonium salts has been synthesized and evaluated for their ability to inhibit neuronal nicotinic acetylcholine receptors (nAChRs) mediating nicotineevoked [ 3 H]dopamine release from superfused rat striatal slices and for inhibition of [ 3 H]nicotine and [ 3 H]methyllycaconitine binding to whole rat brain membranes. The 3-picolinium compound 1,3,5-tri-{5-[1-(3-picolinium)]-pent-1-ynyl}benzene tribromide (tPy3PiB), 3b exhibited high potency and selectivity for nAChR subtypes mediating nicotine-evoked [ 3 H]dopamine release with an IC 50 of 0.2 nM and Imax of 67%.Neuronal nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels composed of five (α and/or β) subunits, each spanning the membrane four times and aligning around the central ion channel. [1][2][3] To date, ten α (α1-α10) and four β (β1-β4) subunits have been identified. 4 Combinations of different subunits establish the various nAChR subtypes, and have distinct pharmacological profiles. 5,6 Activation of specific subtypes of nAChRs contributes to the reinforcing effects of nicotine by stimulating release of the neurotransmitter dopamine (DA). 7-13 Nicotine-evoked DA release is calciumdependent and is blocked completely by the classical nAChR inhibitors, mecamylamine and DHβE, demonstrating that this effect is a direct action at nAChRs. 10 Subtype-selective nAChR antagonists which inhibit nicotine-evoked DA release, have been proposed as potential therapeutic agents for nicotine addiction. [14][15][16][17] To date, the nAChR subtype(s) mediating nicotine-evoked DA release and the mechanism of inhibition of the inhibitors at this receptor subtype have not been elucidated conclusively. Also, in contrast to extensive research on subtype-selective nAChR agonists, less attention has focused on the development of subtype-selective nAChR antagonists. 16,17 The availability of subtypeselective nAChR antagonists would augment the identification of the antagonist pharmacophore(s) for the nAChR subtype(s) mediating nicotine-evoked DA release. Moreover, such subtype-selective antagonists may have potential as treatments for nicotine dependence.© 2007 Elsevier Ltd. All rights reserved.Correspondence to: Peter A. Crooks. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Previous studies from our laboratories have identified N,N '-dodecane-1,12-diyl-bis-3picolinium dibromide (bPiDDB; 1; Figure 1) as a potent inhibitor (IC 50 = 5 nM) of nAChRs mediating nicotine-evoked [ 3 H]DA release from superfused rat striatal slices. 18,19 In vivo microdialysis studies...

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“…Utilizing this extended or linear low energy conformation, a QSAR model utilizing a back-propagation artificial neural network approach has been constructed and has been found to afford good predictivity for inhibition of nicotine-evoked DA release. 27 The hypothesis that bPiDDB binds to nAChR subtype(s) mediating nicotine-evoked DA release in a 'linear' or 'extended' conformation is supported by experimentally determined data 23 showing that analogues with shorter N-N alkyl linker units have decreased inhibitory potency compared to bPiDDB. In the present study, we designed a series of model compounds which mimic different binding conformations of bPiDDB to provide further information on the active conformation of this novel nAChR antagonist.…”

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confidence: 97%

“…Energy minimization calculations reveal that the lowest energy conformation of bPiDDB is one in which the N-N alkyl linker is fully extended. 27 However, the low energy conformations of ligand molecules may not always reflect the conformation in which the molecule binds to the receptor. Utilizing this extended or linear low energy conformation, a QSAR model utilizing a back-propagation artificial neural network approach has been constructed and has been found to afford good predictivity for inhibition of nicotine-evoked DA release.…”

mentioning

confidence: 99%

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

Zheng

Zhang

Pivavarchyk

et al. 2007

Bioorganic & Medicinal Chemistry Letters

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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. KeywordsNicotinic acetylcholine receptor; Quaternary ammonium; Dopamine release; Nicotine addiction Tobacco contains one of the most widely abused psychoactive substances in the world, that is, (S)-nicotine (1; Fig. 1), which is believed to be primarily responsible for tobacco dependence. 1,2 Like many abused drugs, nicotine addiction has been linked to the release of the neurotransmitter, dopamine (DA). [3][4][5] Nicotine-evoked DA release, which is thought to be responsible for reward, leading to addiction, is believed to result from activation of presynaptic neuronal nicotinic acetylcholine receptors (nAChRs). [6][7][8][9][10][11][12] Nicotine stimulates all known nAChR subtypes 13 and upon activation, these receptors modulate the release of various neurotransmitters. [14][15][16] The subunit composition of nAChR subtypes responsible for mediating nicotine-evoked DA release has not been elucidated conclusively. 17 In this regard, subtype-selective nAChR antagonists, which inhibit nicotine-evoked DA release, may have potential as novel treatments for nicotine addiction. [18][19][20][21] Previous work in our laboratories has led to the discovery of N, N′-dodecane-1,12-diyl-bis-3picolinium dibromide (bPiDDB; 2; Fig. 1), which potently inhibited nAChR subtype(s) mediating nicotine-evoked [ 3 H]DA release from superfused rat striatal slices in vitro (IC 50 = 5 nM), and did not interact at the ligand binding site of either α4β2 * or α7 * nAChRs. 22,23 In vivo microdialysis studies demonstrated that pretreatment with bPiDDB dose-dependently reduced the increase in extracellular DA in rat nucleus accumbens produced by acute or repeated nicotine treatment. 24 nature and polarity of the molecule, bPiDDB is brain bioavailable, due to its facilitated transport via the blood-brain barrier choline transporter. 25 Moreover, behavioral studies in rats showed that bPiDDB dose-dependently decreased intravenous nicotine selfadministration, but not sucrose-maintained responding, suggesting a specific inhibition of nicotine reward. 26 Taken together, bPiDDB and its analogues represent lead compounds for the development of a new class of therapeutic agents for the treatment of tobacco dependence.bPiDDB (2) contains two 3-picolinium head groups connected via an N-N-12-methylene linker unit; thus, it is a highly flexible, di-cationic molecule. A better understan...

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QSAR modeling of mono- and bis-quaternary ammonium salts that act as antagonists at neuronal nicotinic acetylcholine receptors mediating dopamine release

Cited by 52 publications

References 35 publications

A simple 2D-QSPR model for the prediction of Setschenow constants of organic compounds

A simple 2D-QSPR model for the prediction of Setschenow constants of organic compounds

tris-Azaaromatic quaternary ammonium salts: Novel templates as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release

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

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