Synthesis and structure–activity relationships of indole and benzimidazole piperazines as histamine H4 receptor antagonists

Terzioglu, Nalan; Rijn, Richard M. van; Bakker, Remko A.; Esch, Iwan J. P. de; Leurs, Rob

doi:10.1016/j.bmcl.2004.08.035

Cited by 108 publications

(79 citation statements)

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“…This modulation of the pain perception was related to an interaction with histamine H4 receptors since the antinociception was antagonized by JNJ 10191584, a potent and selective H4 receptor antagonist (Terzioglu et al, 2004), at a concentration devoid of any effect on pain threshold when administered alone. The involvement of other neurotransmission systems can be ruled out since the VUF 8430-induced thermal antinociception was unmodified by the treatment with the opioid antagonist naloxone, the a 2 -adrenoceptor antagonist yohimbine, the muscarinic antagonist atropine, the nicotinic antagonist mecamylamine.…”

Section: Discussionmentioning

confidence: 99%

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Pleiotropic effect of histamine H4 receptor modulation in the central nervous system

2013

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a b s t r a c tThe histamine H4 receptor (H4R) is expressed primarily on cells involved in inflammation and immune responses. Recently, it has been reported the functional expression of H4R within neurons of the central nervous system, but their role has been poorly understood. The present study aimed to elucidate the physiopathological role of cerebral H4R in animal models by the intracerebroventricular administration of the H4R agonist VUF 8430 (20e40 mg per mouse). Selectivity of results was confirmed by the prevention of the effects produced by the H4R antagonist JNJ 10191584 (3e9 mg/kg p.o.). Neuronal H4R activation induced acute thermal antinociception, indicating that neuronal histamine H4R might be involved in the production of antinociception in the absence of an inflammatory process. An anxiolyticlike effect of intensity comparable to that exerted by diazepam, used as reference drug, was produced in the lightedark box test. VUF 8430 reversed the scopolamine-induced amnesia in the passive avoidance test and showed anorexant activity in food deprived mice. Conversely, the H4R activation did not modify the immobility time in the tail suspension test. Rotarod performance test was employed to demonstrate that the effects observed following the administration of VUF 8430 and JNJ 10191584 were not due to impaired motor function of animals. Furthermore, both compounds did not alter spontaneous mobility and exploratory activity in the hole board test. These results show the antinociceptive, antiamnesic, anxiolytic and anorexant effects induced by neuronal H4R agonism, suggesting that H4 modulators may have broader utility further the control of inflammatory and immune processes.

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Section: Discussionmentioning

confidence: 99%

“…For these reasons, the present study used VUF 8430, a H4 agonist (Lim et al, 2009), and JNJ 10191584 (also known as VUF 6002), a potent and selective H4 antagonist (Terzioglu et al, 2004), to explore the cerebral role of the H4R.…”

Section: Introductionmentioning

confidence: 99%

Pleiotropic effect of histamine H4 receptor modulation in the central nervous system

2013

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“…In the early studies, the H 3 R antagonist thioperamide was identified as an equally effective H 4 R antagonist (Oda et al, 2000;Hough, 2001). High-throughput screening and subsequent medicinal chemistry efforts recently identified the indolylpiperazine JNJ 7777120 (Jablonowski et al, 2003;Thurmond et al, 2004) and the related benzimidazole analog VUF 6002 (Terzioglu et al, 2004) as selective and potent H 4 R antagonists. Studies directed toward selective H 4 R agonists have so far been less successful.…”

Section: Abbreviationsmentioning

confidence: 99%

Evaluation of Histamine H₁-, H₂-, and H₃-Receptor Ligands at the Human Histamine H₄ Receptor: Identification of 4-Methylhistamine as the First Potent and Selective H₄ Receptor Agonist

Lim

Rijn

Ling³

et al. 2005

J Pharmacol Exp Ther

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270

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The histamine H 4 receptor (H 4 R) is involved in the chemotaxis of leukocytes and mast cells to sites of inflammation and is suggested to be a potential drug target for asthma and allergy. So far, selective H 4 R agonists have not been identified. In the present study, we therefore evaluated the human H 4 R (hH 4 R) for its interaction with various known histaminergic ligands. Almost all of the tested H 1 R and H 2 R antagonists, including several important therapeutics, displaced less than 30% of specific [3 H]histamine binding to the hH 4 R at concentrations up to 10 M. Most of the tested H 2 R agonists and imidazolebased H 3 R ligands show micromolar-to-nanomolar range hH 4 R affinity, and these ligands exert different intrinsic hH 4 R activities, ranging from full agonists to inverse agonists. Interestingly, we identified 4-methylhistamine as a high-affinity H 4 R ligand (K i ϭ 50 nM) that has a Ͼ100-fold selectivity for the hH 4 R over the other histamine receptor subtypes. Moreover, 4-methylhistamine potently activated the hH 4 R (pEC 50 ϭ 7.4 Ϯ 0

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“…H4R shows 35% homology to H3R. H4R [7,[15][16][17][18][19][20] mainly distributes in hematopoietic cells and plays a key role in nociceptive responses, autoimmune disorder, allergic conditions, colon cancer, and breast cancer. H4R belongs to the super family of GPCR.…”

Section: Introductionmentioning

confidence: 99%

Virtual Screening, Pharmacophore Modeling, and Quantitative Structure Activity Relationship Studies on Histamine 4 Receptor

Shobana

2017

Asian J Pharm Clin Res

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Objective: To find out novel inhibitors for histamine 4 receptor (H4R), the target for various allergic and inflammatory pathophysiological conditions. Methods: Homology modeling of H4R was performed using easy modeler and validated using structure analysis and verification server, and with the modeled structure, virtual screening, pharmacophore modeling, and quantitative structure activity relationship (QSAR) studies were performed using the Schrodinger 9.3 software.Results: Among all the synthetic and natural ligands, hesperidin, vitexin, and diosmin were found to have the highest dock score, and with that, a five-point pharmacophore model was developed consisting of two hydrogen bond acceptor and three ring atoms, and the pharmacophore hypothesis yielded a statistically significant three-dimensional QSAR (3D-QSAR) model with a correlation coefficient of r 2 =0.8962 as well as good predictive power. Conclusion:The pharmacophore-based 3D-QSAR model generated from natural antihistamines can provide intricate structural knowledge about a new class of anti-allergic and anti-inflammatory drug research.

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Synthesis and structure–activity relationships of indole and benzimidazole piperazines as histamine H4 receptor antagonists

Cited by 108 publications

References 28 publications

Pleiotropic effect of histamine H4 receptor modulation in the central nervous system

Pleiotropic effect of histamine H4 receptor modulation in the central nervous system

Evaluation of Histamine H₁-, H₂-, and H₃-Receptor Ligands at the Human Histamine H₄ Receptor: Identification of 4-Methylhistamine as the First Potent and Selective H₄ Receptor Agonist

Virtual Screening, Pharmacophore Modeling, and Quantitative Structure Activity Relationship Studies on Histamine 4 Receptor

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Synthesis and structure–activity relationships of indole and benzimidazole piperazines as histamine H4 receptor antagonists

Cited by 108 publications

References 28 publications

Pleiotropic effect of histamine H4 receptor modulation in the central nervous system

Pleiotropic effect of histamine H4 receptor modulation in the central nervous system

Evaluation of Histamine H1-, H2-, and H3-Receptor Ligands at the Human Histamine H4 Receptor: Identification of 4-Methylhistamine as the First Potent and Selective H4 Receptor Agonist

Virtual Screening, Pharmacophore Modeling, and Quantitative Structure Activity Relationship Studies on Histamine 4 Receptor

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Evaluation of Histamine H₁-, H₂-, and H₃-Receptor Ligands at the Human Histamine H₄ Receptor: Identification of 4-Methylhistamine as the First Potent and Selective H₄ Receptor Agonist