A Qualitative Model for the Histamine H3 Receptor Explaining Agonistic and Antagonistic Activity Simultaneously

Esch, Iwan J. P. de; Timmerman, Henk; Menge, W.M.P.B.; Nederkoorn, Paul H. J.

doi:10.1002/1521-4184(20008)333:8<254::aid-ardp254>3.0.co;2-g

Cited by 27 publications

(4 citation statements)

References 37 publications

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“…Although in most studies so far published [16,18,27] the imidazole-moiety of antagonists was assumed to interact with E5.46, an inverse placement was assumed in this work for antagonists containing no further basic moieties in their side-chain, resulting in a placement where the imidazole moiety interacted with D3.32. In our opinion, this hypothesis is supported by the binding affinities measured for the antagonists ciproxifan, thioperamide, clobenpropit and NNC-0038-1035 described by Jacobsen et al [23].…”

Section: Discussionmentioning

confidence: 99%

“…Several in silico studies have already been carried out on the hH 3 R focusing however mainly on the placement of ligands in the binding pocket and on the derivation of a putative binding site for reasoning the design of new compounds rather than on an automatic screening for new compounds. In 2000 De Esch et al [16,17] published a study on imidazole-containing hH 3 R ligands and proposed a pharmacophore model consisting of a common anchor site for the imidazole moiety which was expected to interact with E5.46 in helix 5, and two lipophilic pockets. At the same time branched compounds published by Schering in the patent application WO00/53596 confirmed the existence of two lipophilic pockets.…”

Section: Introductionmentioning

confidence: 99%

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Generation of a homology model of the human histamine H3 receptor for ligand docking and pharmacophore-based screening

Schlegel

Laggner

Meier

et al. 2007

J Comput Aided Mol Des

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The human histamine H 3 receptor (hH 3 R) is a G-protein coupled receptor (GPCR), which modulates the release of various neurotransmitters in the central and peripheral nervous system and therefore is a potential target in the therapy of numerous diseases. Although ligands addressing this receptor are already known, the discovery of alternative lead structures represents an important goal in drug design. The goal of this work was to study the hH 3 R and its antagonists by means of molecular modelling tools. For this purpose, a strategy was pursued in which a homology model of the hH 3 R based on the crystal structure of bovine rhodopsin was generated and refined by molecular dynamics simulations in a dipalmitoylphosphatidylcholine (DPPC)/water membrane mimic before the resulting binding pocket was used for high-throughput docking using the program GOLD. Alternatively, a pharmacophore-based procedure was carried out where the alleged bioactive conformations of three different potent hH 3 R antagonists were used as templates for the generation of pharmacophore models. A pharmacophore-based screening was then carried out using the program Catalyst. Based upon a database of 418 validated hH 3 R antagonists both strategies could be validated in respect of their performance. Seven hits obtained during this screening procedure were commercially purchased, and experimentally tested in a [ 3 H]N a -methylhistamine binding assay. The compounds tested showed affinities at hH 3 R with K i values ranging from 0.079 to 6.3 lM.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Generation of a homology model of the human histamine H3 receptor for ligand docking and pharmacophore-based screening

Schlegel

Laggner

Meier

et al. 2007

J Comput Aided Mol Des

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“…Ethanol and isopropyl alcohol were used only in multicomponent solutions for impregnation of plates. The choice of model compounds for the binding elements in the receptor structure was based on the literature data on the use of the propionic acid structure in studies of the interaction of aspartic acid with the ligands of the histamine H 3 receptor [33, 34]. …”

Section: Resultsmentioning

confidence: 99%

Development and Validation of Quantitative Structure-Activity Relationship Models for Compounds Acting on Serotoninergic Receptors

Żydek

Brzezińska

2012

The Scientific World Journal

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A quantitative structure-activity relationship (QSAR) study has been made on 20 compounds with serotonin (5-HT) receptor affinity. Thin-layer chromatographic (TLC) data and physicochemical parameters were applied in this study. RP2 TLC 60F254 plates (silanized) impregnated with solutions of propionic acid, ethylbenzene, 4-ethylphenol, and propionamide (used as analogues of the key receptor amino acids) and their mixtures (denoted as S1–S7 biochromatographic models) were used in two developing phases as a model of drug-5-HT receptor interaction. The semiempirical method AM1 (HyperChem v. 7.0 program) and ACD/Labs v. 8.0 program were employed to calculate a set of physicochemical parameters for the investigated compounds. Correlation and multiple linear regression analysis were used to search for the best QSAR equations. The correlations obtained for the compounds studied represent their interactions with the proposed biochromatographic models. The good multivariate relationships (R 2 = 0.78–0.84) obtained by means of regression analysis can be used for predicting the quantitative effect of biological activity of different compounds with 5-HT receptor affinity. “Leave-one-out” (LOO) and “leave-N-out” (LNO) cross-validation methods were used to judge the predictive power of final regression equations.

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“…Chromatography. In this study we investigated the role of interaction between the examined thiazole and benzothiazole derivatives, the selected H 1 -, H 2 -antihistamine drugs and l-Asp and propionic acid [selected according to the proposed (Hill et al, 1997;De Esch et al, 2000;Windhorst et al, 2000) agonistic and antagonistic binding site models of histamine receptors] in chromatographic environment.…”

Section: Structures Of the Examined Compounds 1-49mentioning

confidence: 99%

A structure–activity relationship study of compounds with antihistamine activity

Brzezińska

Kośka

2006

Biomedical Chromatography

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A structure-activity relationship (SAR) analysis of H(1)-, H(2)- and H(3)-antihistamine activity was carried out and chromatographic data of 2-[2-(phenylamino)thiazol-4-yl]ethanamine, 2-(2-benzyl-4-thiazolyl)ethanamine, 2-(2-benzhydrylthiazol4-yl)ethanamine, 2-(1-piperazinyl- and 2-(hexahydro-1H-1,4-diazepin-1-yl)benzothiazole, 2-(1-piperazinyl)benzothiazole, 2-[4-(1-alkyl)piperidinyl]benzothiazole, 2-(N,N',N'-dimethylalkyl-1,2-ethanediamino)benzothiazole, 2[1-(4-aminopiperidinyl)]benzothiazole, 2-[2-phenyl-4-thiazolyl]ethanamine derivatives and selected H(1)- and H(2)-antihistamine drugs were obtained. NP TLC and RP2 TLC plates (silica gel NP 60F(254) and silica gel RP2 60F(254) silanized precoated), impregnated with a solution of aspartic acid (L-Asp) and a solution of an analogue of aspartic acid (propionic acid), were used in two developing solvents as H(1)-, H(2)- and H(3)-antihistaminic interaction models. The lipophilicity data of the examined compounds were obtained and used in the SAR assay. Biochromatographic tests using TLC plates impregnated with solutions of asparic acid or propionic acid were found to be a source of useful data for the qualitative analysis of compounds with different structures, demonstrating activity to histamine H(1)-, H(2)- and H(3)-receptors. The four presented discriminant models based on biochromatographic studies are an efficient tool in the SAR analysis for initial prediction of compound activity direction within histamine receptors.

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A Qualitative Model for the Histamine H3 Receptor Explaining Agonistic and Antagonistic Activity Simultaneously

Cited by 27 publications

References 37 publications

Generation of a homology model of the human histamine H3 receptor for ligand docking and pharmacophore-based screening

Generation of a homology model of the human histamine H3 receptor for ligand docking and pharmacophore-based screening

Development and Validation of Quantitative Structure-Activity Relationship Models for Compounds Acting on Serotoninergic Receptors

A structure–activity relationship study of compounds with antihistamine activity

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