Pharmacological Differences between Human and Guinea Pig Histamine H1 Receptors: Asn84 (2.61) as Key Residue within an Additional Binding Pocket in the H1 Receptor

Bruysters, Martijn; Jongejan, Aldo; Gillard, Michel; Manakker, Frank van de; Bakker, Remko A.; Chatelain, Pierre; Leurs, Rob

doi:10.1124/mol.104.008847

Cited by 46 publications

(49 citation statements)

References 33 publications

(58 reference statements)

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“…Human and guinea pig H1R models based on the bovine rhodopsin structure were also published [16]. Several known agonists and antagonists were docked and complexes were further refined by MD simulations.…”

Section: H1 Receptormentioning

confidence: 99%

Structure-based discovery and binding site analysis of histamine receptor ligands

Kingsford-Adaboh

Keserü

2016

Expert Opinion on Drug Discovery

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Introduction: Application of structure-based drug discovery in histamine receptor projects was previously hampered by the lack of experimental structures. The publication of the first X-ray structure of the histamine H1 receptor has been followed by several successful virtual screens and binding site analysis studies of H1-antihistamines. This structure together with several other recently solved aminergic G-protein coupled receptors (GPCRs) enabled the development of more realistic homology models for H2, H3 and H4 receptors. Areas covered: In this paper, we review the development of histamine receptors models and their application on drug discovery. Expert opinion: In our opinion, the application of atomistic histamine receptor models played a significant role in understanding key ligand-receptor interactions as well as in the discovery of novel chemical starting points. The recently solved H1 receptor structure is a major milestone in structure-based drug discovery, however our analysis also demonstrate that for building H3 and H4 receptor homology models other GPCRs may be more suitable as a template. For these receptors we envisage that the development of higher quality homology models will significantly contribute to the discovery and optimization of novel H3 and H4 ligands.

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Section: H1 Receptormentioning

confidence: 99%

Structure-based discovery and binding site analysis of histamine receptor ligands

Kingsford-Adaboh

Keserü

2016

Expert Opinion on Drug Discovery

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“…Unfortunately, bulky H 1 R agonists exhibit considerably lower potency and efficacy at the hH 1 R than at the guinea pig H 1 R (gpH 1 R), limiting their usefulness as tools for studying the hH 1 R (Seifert et al, 2003). The molecular basis for the differences in pharmacological properties between hH 1 R and gpH 1 R has recently been elucidated (Bruysters et al, 2005). A further complication is that, at concentrations in the range of 10 M to 1 mM, 2-phenylhistamines may activate G-proteins directly, i.e., in a receptor-independent manner (Seifert et al, 1994;Hagelü ken et al, 1995;Klinker et al, 1996).…”

mentioning

confidence: 99%

N¹-(3-Cyclohexylbutanoyl)-N²-[3-(1H-imidazol-4-yl)propyl]guanidine (UR-AK57), a Potent Partial Agonist for the Human Histamine H₁- and H₂-Receptors

Xie¹,

Kraus²,

Ghorai³

et al. 2006

J Pharmacol Exp Ther

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Both the histamine H 1 -receptor (H 1 R) and H 2 -receptor (H 2 R) exhibit pronounced species selectivity in their pharmacological properties; i.e., bulky agonists possess higher potencies and efficacies at guinea pig (gp) than at the corresponding human (h) receptor isoforms. In this study, we examined the effects of N G -acylated imidazolylpropylguanidines substituted with a single phenyl or cyclohexyl substituent on H 1 R and H 2 R species isoforms expressed in Sf9 insect cells. 1H-imidazol-4-yl)propyl]guanidine (UR-AK57) turned out to be the most potent hH 2 R agonist identified so far (EC 50 of 23 nM in the GTPase assay at the hH 2 R-G s␣ fusion protein expressed in Sf9 insect cells). UR-AK57 was almost a full-hH 2 R agonist and only slightly less potent and efficacious than at gpH 2 R-G s␣ . Several N G -acylated imidazolylpropylguanidines showed similar potency at hH 2 R and gpH 2 R. Most unexpectedly, UR-AK57 exhibited moderately strong partial hH 1 R agonism with a potency similar to that of histamine, whereas at gpH 1 R, UR-AK57 was only a very weak partial agonist. Structure/activity relationship studies revealed that both the alkanoyl chain connecting the aromatic or alicyclic substituent with the guanidine moiety and the nature of the carbocycle (cyclohexyl versus phenyl ring) critically determine the pharmacological properties of this class of compounds. Collectively, our data show that gpH 1 R and gpH 2 R do not necessarily exhibit preference for bulky agonists compared with hH 1 R and hH 2 R, respectively, and that UR-AK57 is a promising starting point for the development of both potent and efficacious hH 1 R and hH 2 R agonists.Histamine (HIS) (1) (see Fig. 1) is a neurotransmitter and autacoid and acts through H 1 -, H 2 -, H 3 -, and H 4 -receptors (H 1 R-H 4 R) (Hill et al., 1997;Hough, 2001;Bakker et al., 2002). The H 1 R couples to G q -proteins to mediate phospholipase C activation and plays a role in the regulation of alertness and as mediator of type 1 allergic reactions (Hill et al., 1997;Bakker et al., 2002). The H 2 R couples to G s -proteins to mediate adenylyl cyclase activation and regulates H ϩ secretion in gastric parietal cells, cardiac contractility, and various myeloid cell functions (Klinker et al., 1996;Hill et al., 1997;Bakker et al., 2002).It has been difficult to establish relevant native test systems for the analysis of the human H 1 R (hH 1 R) and human H 2 R (hH 2 R), because there are unexplained pharmacological differences in the properties of hH 1 R and hH 2 R in native cells relative to standard guinea pig test organs (Burde et al., 1990;Seifert et al., 1994;Klinker et al., 1996). To facilitate the comparison of histamine receptors under identical experimental conditions, we established expression systems for the H 1 R and H 2 R in Sf9 insect cells Houston et al., 2002). Sf9 cells express the H 1 R and H 2 R at high levels and can be cultured in large quantities. GPCR/Gprotein coupling in Sf9 membranes is monitored with high sensitivity using the steady-sta...

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“…Several mutational studies identified amino acids interacting with antagonists in the H 1 R binding pocket (Wieland et al, 1999) and amino acids responsible for species differences between hH 1 R and gpH 1 R (Bruysters et al, 2005;Strasser et al, 2008b) concerning agonists. Because there has been no thermodynamic study of ligand binding to the H 1 R, the aim of this study was to analyze the following questions: 1) Is there a thermodynamic discrimination between agonists and antagonists at hH 1 R and gpH 1 R?…”

mentioning

confidence: 99%

Contribution of Binding Enthalpy and Entropy to Affinity of Antagonist and Agonist Binding at Human and Guinea Pig Histamine H₁-Receptor

Wittmann

Seifert²,

Straßer³

2009

Mol Pharmacol

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For several GPCRs, discrimination between agonism and antagonism is possible on the basis of thermodynamics parameters, such as binding enthalpy and entropy. In this study, we analyze whether agonists and antagonists can also be discriminated thermodynamically at the histamine H 1 receptor (H 1 R). Because previous studies revealed species differences in pharmacology between human H 1 R (hH 1 R) and guinea pig H 1 R (gpH 1 R), we analyzed a broad spectrum of H 1 R antagonists and agonists at hH 1 R and gpH 1 R. [3 H]Mepyramine competition binding assay were performed at five different temperatures in a range from 283.15 to 303.15 K. In addition, we performed a temperature-dependent three-dimensional quantitative structure activity relationship study to predict binding enthalpy and entropy for histaprodifen derivatives, which can bind to H 1 R in two different orientations. Our studies revealed significant species differences in binding enthalpy and entropy between hH 1 R and gpH 1 R for some antagonists and agonists. Furthermore, in some cases, we found changes in heat capacity of the binding process that were different from zero. Differences in flexibility of the ligands may be responsible for this observation. For most ligands, the binding process to hH 1 R and gpH 1 R is clearly entropy-driven. In contrast, for the endogenous ligand histamine, the binding process is significantly enthalpy-driven at both species isoforms. Thus, a definite discrimination between antagonism and agonism based on thermodynamic parameters is possible for neither hH 1 R nor gpH 1 R, but thermodynamic analysis of ligand-binding may be a novel approach to dissect agonist-and antagonist-specific receptor conformations.

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Pharmacological Differences between Human and Guinea Pig Histamine H₁ Receptors: Asn⁸⁴ (2.61) as Key Residue within an Additional Binding Pocket in the H₁ Receptor

Cited by 46 publications

References 33 publications

Structure-based discovery and binding site analysis of histamine receptor ligands

Structure-based discovery and binding site analysis of histamine receptor ligands

N¹-(3-Cyclohexylbutanoyl)-N²-[3-(1H-imidazol-4-yl)propyl]guanidine (UR-AK57), a Potent Partial Agonist for the Human Histamine H₁- and H₂-Receptors

Contribution of Binding Enthalpy and Entropy to Affinity of Antagonist and Agonist Binding at Human and Guinea Pig Histamine H₁-Receptor

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Pharmacological Differences between Human and Guinea Pig Histamine H1 Receptors: Asn84 (2.61) as Key Residue within an Additional Binding Pocket in the H1 Receptor

Cited by 46 publications

References 33 publications

Structure-based discovery and binding site analysis of histamine receptor ligands

Structure-based discovery and binding site analysis of histamine receptor ligands

N1-(3-Cyclohexylbutanoyl)-N2-[3-(1H-imidazol-4-yl)propyl]guanidine (UR-AK57), a Potent Partial Agonist for the Human Histamine H1- and H2-Receptors

Contribution of Binding Enthalpy and Entropy to Affinity of Antagonist and Agonist Binding at Human and Guinea Pig Histamine H1-Receptor

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Product

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Pharmacological Differences between Human and Guinea Pig Histamine H₁ Receptors: Asn⁸⁴ (2.61) as Key Residue within an Additional Binding Pocket in the H₁ Receptor

N¹-(3-Cyclohexylbutanoyl)-N²-[3-(1H-imidazol-4-yl)propyl]guanidine (UR-AK57), a Potent Partial Agonist for the Human Histamine H₁- and H₂-Receptors

Contribution of Binding Enthalpy and Entropy to Affinity of Antagonist and Agonist Binding at Human and Guinea Pig Histamine H₁-Receptor