Detailed structure–activity relationship of indolecarboxamides as H4 receptor ligands

Engelhardt, Harald; Esch, Iwan J. P. de; Kühn, Daniel; Smits, Rogier A.; Zuiderveld, Obbe P.; Dobler, Julia; Mayer, Moriz; Lips, Sebastian; Arnhof, Heribert; Scharn, Dirk; Haaksma, Eric E. J.; Leurs, Rob

doi:10.1016/j.ejmech.2012.06.016

Cited by 17 publications

(21 citation statements)

References 24 publications

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“…The 47 β‐arrestin2‐biased indolecarboxamides displayed a wide variation in potencies and intrinsic activities. The potencies correlated with previously published affinities (Engelhardt et al ., ), which is in line with earlier observations that β‐arrestin2 signalling is correlated with receptor occupancy and in line with the 1:1 stoichiometry of receptor and β‐arrestin2 interaction in an enzyme fragment‐based complementation assay (Granier et al ., ; Kruse et al ., ; Riddy et al ., ; Shoichet and Kobilka, ). No correlation was observed between affinity and intrinsic activities, making it worthwhile to identify the structural requirements for intrinsic activity.…”

Section: Discussionsupporting

confidence: 92%

“…Potency values of all tested indolecarboxamides to stimulate β‐arrestin2 recruitment to hH 4 R are linearly correlated with their hH 4 R binding affinity values that we previously reported (Engelhardt et al ., ) (slope = 1.1 ± 0.1, R 2 = 0.89) (Figure A). In contrast, no correlation was observed between intrinsic activity and affinity values (Figure B).…”

Section: Resultsmentioning

confidence: 94%

“…Schild analysis (slope = 0.9 ± 0.1) showed that 75 and 1 (JNJ 7777120) interact with hH 4 R in a competitive manner (Figure D). Moreover, the pA 2 (8.5) of 1 (JNJ 7777120) closely resembled its pK i (8.3) for the hH 4 R (Engelhardt et al ., ).…”

Section: Resultsmentioning

confidence: 97%

“…Based on our dataset, we observed that β‐arrestin2 activation of the tested indolecarboxamides is less dependent on such polar interactions than Gα i protein signalling. In a previous quantitative structure– affinity relationship study, the position R7 tolerated both lipophilic and polar moieties (Engelhardt et al ., ). Yet, in the present study, we show that (hydrophobic) substituents at this position are less favourable for biased β‐arrestin2 recruitment.…”

Section: Discussionmentioning

confidence: 97%

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Detailed analysis of biased histamine H₄ receptor signalling by JNJ 7777120 analogues

Nijmeijer¹,

Vischer²,

Sirci

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSEThe histamine H4 receptor, originally thought to signal merely through Gai proteins, has recently been shown to also recruit and signal via b-arrestin2. Following the discovery that the reference antagonist indolecarboxamide JNJ 7777120 appears to be a partial agonist in b-arrestin2 recruitment, we have identified additional biased hH4R ligands that preferentially couple to Gai or b-arrestin2 proteins. In this study, we explored ligand and receptor regions that are important for biased hH4R signalling. EXPERIMENTAL APPROACHWe evaluated a series of 48 indolecarboxamides with subtle structural differences for their ability to induce hH4R-mediated Gai protein signalling or b-arrestin2 recruitment. Subsequently, a Fingerprints for Ligands and Proteins three-dimensional quantitative structure-activity relationship analysis correlated intrinsic activity values with structural ligand requirements. Moreover, a hH4R homology model was used to identify receptor regions important for biased hH4R signalling. KEY RESULTSOne indolecarboxamide (75) with a nitro substituent on position R7 of the aromatic ring displayed an equal preference for the Gai and b-arrestin2 pathway and was classified as unbiased hH4R ligand. The other 47 indolecarboxamides were b-arrestin2-biased agonists. Intrinsic activities of the unbiased as well as b-arrestin2-biased indolecarboxamides to induce b-arrestin2 recruitment could be correlated with different ligand features and hH4R regions. CONCLUSION AND IMPLICATIONSSmall structural modifications resulted in diverse intrinsic activities for unbiased (75) and b-arrestin2-biased indolecarboxamides. Analysis of ligand and receptor features revealed efficacy hotspots responsible for biased-b-arrestin2 recruitment. This knowledge is useful for the design of hH4R ligands with biased intrinsic activities and aids our understanding of the mechanism of H4R activation.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

See 2 more Smart Citations

Detailed analysis of biased histamine H₄ receptor signalling by JNJ 7777120 analogues

Nijmeijer¹,

Vischer²,

Sirci

et al. 2013

British J Pharmacology

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“…Clinical studies on H4 receptor antagonists are currently ongoing (Engelhardt et al, 2009). Misery (2008) approached the intriguing parallelism between itch/scratching and cough starting from a common pathophysiology that involves the C fibres, the mast cells, histamine, SP and other tachykinins.…”

Section: Figurementioning

confidence: 99%

The role of histamine in neurogenic inflammation

Rosa

Fantozzi

2013

British J Pharmacology

163

138

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The term 'neurogenic inflammation' has been adopted to describe the local release of inflammatory mediators, such as substance P and calcitonin gene-related peptide, from neurons. Once released, these neuropeptides induce the release of histamine from adjacent mast cells. In turn, histamine evokes the release of substance P and calcitonin gene-related peptide; thus, a bidirectional link between histamine and neuropeptides in neurogenic inflammation is established. The aim of this review is to summarize the most recent findings on the role of histamine in neurogenic inflammation, with particular regard to nociceptive pain, as well as neurogenic inflammation in the skin, airways and bladder. LINKED ARTICLESThis article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1 Abbreviations CGRP, calcitonin gene-related peptide; ERs, oestrogen receptors; GERD, gastro-oesophageal reflux disease; HDC, histidine decarboxylase; IC, interstitial cystitis; PBS, painful bladder syndrome; SP, substance P; VIP, vasoactive intestinal peptide IntroductionThe term 'neurogenic inflammation' describes the local release of inflammatory mediators, such as substance P (SP) and calcitonin gene-related peptide (CGRP), from afferent neurons. The initial evidence for neurogenic vasodilatation in response to noxious stimuli was obtained in the skin of humans and other mammals (Schmelz and Petersen, 2001), but now it is recognized that neurogenic inflammation also occurs in visceral organs. The inflammatory response evoked by the activation of the sensory nerve fibres, which includes local vasodilatation, plasma extravasation, leukocyte and platelet adhesion, and mast cell degranulation, is brought about by neuropeptides released from the peripheral endings of sensory neurons upon stimulation of the primary sensory terminals. Both SP in neurons and histamine in mast cells have a dual mediator role in neurogenic inflammation (Figure 1). In fact, as demonstrated by Foreman and Jordan (1984), injury causes activation of sensory nerve endings either directly or through the release of histamine from the adjacent mast cells. The action potential generated travels orthodromically to the dorsal horn of the spinal cord and spreads to other branches of the same neurons, which will then release SP from their terminals or varicosities. The released SP, as well as contributing itself to local vasodilatation, induces histamine release from the adjacent mast cells, which produces flare and further activates other sensory nerve endings (Foreman et al., 1983).Neutrophils, whose responsiveness to SP has been repeatedly demonstrated, contribute to the inflammatory soup following neurogenic inflammation. In fact, neutrophils express the SP receptors NK 1, NK2 and NK3, and when stimulated with SP induce the expression of COX-2 and PGE2 release in the nanomolar range (Gallicchio et al., 2008;. Furthermore, SP at micromolar concentrations primes neutrophils, thus en...

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Synthesis and Functional Characterization of Imbutamine Analogs as Histamine H₃ and H₄ Receptor Ligands

Geyer

Kaske

Baumeister

et al. 2013

Archiv der Pharmazie

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Imbutamine (4-(1H-imidazol-4-yl)butanamine) is a potent histamine H3 (H3R) and H4 receptor (H4R) agonist (EC50 values: 3 and 66 nM, respectively). Aiming at improved selectivity for the H4R, the imidazole ring in imbutamine was methyl-substituted or replaced by various differently substituted heterocycles (1,2,3-triazoles, 1,2,4-triazoles, pyridines, pyrimidines) as potential bioisosteres. Investigations in [(35)S]GTPγS binding assays using membranes of Sf9 insect cells expressing the respective human histamine receptor subtype revealed only very weak activity of most of the synthesized hetarylalkylamines at both receptors. By contrast, the introduction of substituents at the 4-imidazolyl ring was most effective regarding H4R selectivity. This holds for methyl substitution in position 2 and, especially, in position 5. 5-Methylimbutamine (H4R: EC50 = 59 nM, α = 0.8) was equipotent with imbutamine at the hH4R, but revealed about 16-fold selectivity for the hH4R compared to the hH3R (EC50 980 nM, α = 0.36), whereas imbutamine preferred the hH3R. The functional activities were in agreement with radioligand binding data. The results support the hypothesis that, by analogy with histamine, methyl substitution in histamine homologs offers a way to shift the selectivity in favor of the H4R.

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Detailed structure–activity relationship of indolecarboxamides as H4 receptor ligands

Cited by 17 publications

References 24 publications

Detailed analysis of biased histamine H₄ receptor signalling by JNJ 7777120 analogues

Detailed analysis of biased histamine H₄ receptor signalling by JNJ 7777120 analogues

The role of histamine in neurogenic inflammation

Synthesis and Functional Characterization of Imbutamine Analogs as Histamine H₃ and H₄ Receptor Ligands

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Detailed structure–activity relationship of indolecarboxamides as H4 receptor ligands

Cited by 17 publications

References 24 publications

Detailed analysis of biased histamine H4 receptor signalling by JNJ 7777120 analogues

Detailed analysis of biased histamine H4 receptor signalling by JNJ 7777120 analogues

The role of histamine in neurogenic inflammation

Synthesis and Functional Characterization of Imbutamine Analogs as Histamine H3 and H4 Receptor Ligands

Contact Info

Product

Resources

About

Detailed analysis of biased histamine H₄ receptor signalling by JNJ 7777120 analogues

Detailed analysis of biased histamine H₄ receptor signalling by JNJ 7777120 analogues

Synthesis and Functional Characterization of Imbutamine Analogs as Histamine H₃ and H₄ Receptor Ligands