Theoretical Analyses of the Tautomeric and Conformational Equilibria of Histamine and (.alpha.R,.beta.S)-.alpha.,.beta.-Dimethylhistamine in the Gas Phase and Aqueous Solution

Nagy, Péter; Durant, G. J.; Hoss, Wayne; Smith, D.

doi:10.1021/ja00090a040

Cited by 54 publications

(53 citation statements)

References 3 publications

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“…Based on these intensities, the mole fractions of N1-H and N3-H were estimated to be 0.65 and 0.35, respectively. Although these solution phase populations are significantly different from those predicted by Boltzmann statistics, they are in good agreement with solution phase estimates reported in the literature: 0.6-0.65 for N1-H; 0.4-0.35 for N3-H. 39,45 Using the empirically determined mole fractions, VCD and IR spectra were simulated for a tautomeric mixture by multiplying the intensity scales of the VCD and IR spectra predicted for each tautomer by its fractional population then combining the scaled spectra. The VCD and IR spectra predicted for a 65:35 mixture of Models 1 and 2 are included with the Boltzmann data in Figure 5.…”

Section: Resultssupporting

confidence: 88%

“…In the upper panel of this figure, the agreement between the VCD spectrum calculated for Model 2 and experimental is significantly poorer than Model 1, as expected since the N3-H tautomer is the minor form. 39,44,45 Of note is the strong, negatively signed VCD band near 1308 cm 21 which is not present in the VCD spectrum of Model 1. A moderately intense shoulder near this frequency in the experimental VCD spectrum supports the presence of the N3-H tautomer under our experimental conditions.…”

Section: Resultsmentioning

confidence: 96%

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An investigation of the absolute configuration of the potent histamine H3 receptor antagonist GT‐2331 using vibrational circular dichroism

et al. 2007

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GT-2331 [(+)-1] is one of the most potent members of a class of chiral drug substances used to regulate the synthesis and release of histamine by the histamine H3 receptor, and as such, is an important biomarker for pharmaceutical companies conducting research in this field. In addition to overall structural features, the bioactivity of this molecule has also been found to be highly dependent on absolute stereochemistry, making the reliable assignment of this property a necessity. X-ray diffraction studies have provided conflicting data, leaving its three-dimensional structure uncertain. In view of this, its absolute configuration was investigated by vibrational circular dichroism. Results from this study provided independent assignment of this important molecule as the (1S,2S)-enantiomer.

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Section: Resultssupporting

confidence: 88%

Section: Resultsmentioning

confidence: 96%

An investigation of the absolute configuration of the potent histamine H3 receptor antagonist GT‐2331 using vibrational circular dichroism

et al. 2007

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“…Histamine was either positioned in between Asp 98 (TM3) and the Tyr1821Asp186 couple (TM5) or in between Asp 9~ (TM3) and Asp~86IThr'9° (TM5). The main determinants for the interaction between histamine and the histamine H2 receptor were thus assumed to be the earlier-mentioned three hydrogen bonds [9][10][11][12][13][14], one of them having an ionic character (Asp 98 interacting with the positively charged side-chain amino group of histamine). The CHARMm [15,16] force field was used throughout Section II (steps [8][9][10].…”

Section: Methodsmentioning

confidence: 99%

The agonistic binding site at the histamine H2 receptor. II. Theoretical investigations of histamine binding to receptor models of the seven α-helical transmembrane domain

Nederkoorn

Gelder

Kelder

et al. 1996

J Computer-Aided Mol Des

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In the first part (pp. 461-478 in this issue) of this study regarding the histamine H 2 receptor agonistic binding site, the best possible interactions of histamine with an c~-helical oligopeptide, mimicking a part of the fifth transmembrane m-helical domain (TM5) of the histamine H 2 receptor, were considered. It was established that histamine can only bind via two H-bonds with a pure c~-helical TM5, when the binding site consists of Tyr182/Asp186 and not of the AspX86/Thr 19° couple. In this second part, two particular three-dimensional models of G-protein-coupled receptors previously reported in the literature are compared in relation to agonist binding at the histamine H2 receptor. The differences between these two receptor models are discussed in relation to the general benefits and limitations of such receptor models. Also the pros and cons of simplifying receptor models to a relatively easy-to-deal-with oligopeptide for mimicking agonistic binding to an agonistic binding site are addressed. Within complete receptor models, the simultaneous interaction of histamine with both TM3 and TM5 can be analysed. The earlier suggested three-point interaction of histamine with the histamine H z receptor can be explored. Our results demonstrate that a three-point interaction cannot be established for the Asp98/ Asp186/Thr 19° binding site in either of the investigated receptor models, whereas histamine can form three H-bonds in case the agonistic binding site is constituted by the Asp98/TyrX82/Asp ~8~ triplet. Furthermore, this latter triplet is seen to be able to accommodate a series of substituted histamine analogues with known histamine H 2 agonistic activity as well.

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“…A more quantitative approach would also be hampered by the in vacuo formation of intramolecular hydrogen bonds between the proton of the cationic moiety in the side chain of the ligands and the basic N π atom of the imidazole ring ( Figure 5). This intramolecular H-bond artificially lowers the global energy of the ligands, making absolute energy differences between the biologically active conformation and the "global" minimum difficult to assess in a quantitative manner, as has been described in detail by Nagy and co-workers [32] .…”

Section: Coupling Of the Individual Asp Model-pharmacon Complexesmentioning

confidence: 97%

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

Esch

Timmerman

Menge

et al. 2000

Arch. Pharm. Pharm. Med. Chem.

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A pharmacophore model for histamine H3 ligands is derived that reveals the putative interaction of both H3 agonists and antagonists with an aspartate residue of the receptor. This interaction is determined by applying the density functional theory implemented in a program package adapted for parallel computers. The model reveals a molecular determinant explaining efficacy as the conformation of the aspartic acid residue differs according to whether it is binding to agonists or antagonists. The differences in structure‐activity relationships (SAR) observed for the lipophilic tails of different classes of H3 antagonists are now explained, since the model reveals two distinct lipophilic pockets available for antagonist binding.

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Theoretical Analyses of the Tautomeric and Conformational Equilibria of Histamine and (.alpha.R,.beta.S)-.alpha.,.beta.-Dimethylhistamine in the Gas Phase and Aqueous Solution

Cited by 54 publications

References 3 publications

An investigation of the absolute configuration of the potent histamine H3 receptor antagonist GT‐2331 using vibrational circular dichroism

An investigation of the absolute configuration of the potent histamine H3 receptor antagonist GT‐2331 using vibrational circular dichroism

The agonistic binding site at the histamine H2 receptor. II. Theoretical investigations of histamine binding to receptor models of the seven α-helical transmembrane domain

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

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