Synthesis and Histamine H1 Receptor Agonist Activity of a Series of 2-Phenylhistamines, 2-Heteroarylhistamines, and Analogs

Leschke, Christian; Elz, Sigurd; Garbarg, M.; Schunack, Walter

doi:10.1021/jm00008a007

Cited by 64 publications

(61 citation statements)

References 23 publications

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“…7C). For the phenylhistamines, the efficacies are either in the same range at both hH 1 R and hH 4 R or higher at hH 1 R that at hH 4 R. Collectively, 2-phenylhistamines are less selective H 1 R agonists than originally assumed (Leschke et al, 1995;Seifert et al, 2003). Future studies will have to determine whether the previously reported H 1 R and H 2 R antagonist-resistant effects of 2-phenylhistamines in HL-60 leukemia cells are mediated by hH 4 R rather than by the originally assumed receptor-independent direct G-protein activation (Seifert et al, 1994).…”

Section: Discussionmentioning

confidence: 77%

“…We included structurally diverse H 1 R antagonists of the first and second generation as well as antidepressants, acting also as H 1 R antagonists, into our study (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Moreover, we characterized small H 1 R agonists (19)(20)(21)(22)(23)(24) and H 1 R agonists of the phenylhistamine (25-36) and histaprodifen (37-41) classes (Leschke et al, 1995;Kramer et al, 1998;Elz et al, 2000;Menghin et al, 2003) at hH 4 R.…”

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confidence: 99%

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Interactions of Histamine H₁-Receptor Agonists and Antagonists with the Human Histamine H₄-Receptor

Deml

Beermann²,

Neumann³

et al. 2009

Mol Pharmacol

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The human histamine H 4 -receptor (hH 4 R) possesses high constitutive activity and, like the human H 1 -receptor (hH 1 R), is involved in the pathogenesis of type-I allergic reactions. The study aims were to explore the value of dual H 1 /H 4 R antagonists as antiallergy drugs and to address the question of whether H 1 R ligands bind to hH 4 R. In an acute murine asthma model, the H 1 R antagonist mepyramine and the H 4 R antagonist 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methyl-piperazine (JNJ 7777120) exhibited synergistic inhibitory effects on eosinophil accumulation in the bronchoalveolar lavage fluid. At the hH 4 R expressed in Sf9 insect cells, 18 H 1 R antagonists and 22 H 1 R agonists showed lower affinity to hH 4 R than to hH 1 R as assessed in competition binding experiments. For a small number of H 1 R antagonists, hH 4 R partial agonism was observed in the steady-state GTPase assay. Most compounds were neutral antagonists or inverse agonists. Twelve phenylhistamine-type hH 1 R partial agonists were also hH 4 R partial agonists. Four histaprodifen-type hH 1 R partial agonists were hH 4 R inverse agonists. Dimeric histaprodifen was a more efficacious hH 4 R inverse agonist than the reference compound thioperamide. Suprahistaprodifen was the only histaprodifen acting as hH 4 R partial agonist. Suprahistaprodifen was docked into the binding pocket of inactive and active hH 4 R models in two different orientations, predominantly stabilizing the active state of hH 4 R. Collectively, the synergistic effects of H 1 R and H 4 R antagonists in an acute asthma model and the overlapping interaction of structurally diverse H 1 R ligands with hH 1 R and hH 4 R indicate that the development of dual H 1 R/H 4 R antagonists is a worthwhile and technically feasible goal for the treatment of type-I allergic reactions.

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Section: Discussionmentioning

confidence: 77%

mentioning

confidence: 99%

Interactions of Histamine H₁-Receptor Agonists and Antagonists with the Human Histamine H₄-Receptor

Deml

Beermann²,

Neumann³

et al. 2009

Mol Pharmacol

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“…2-Methylhistamine (2) and 2-(2-thiazolyl)ethanamine (3) were synthesized using standard procedures. Compounds 5 to 18 were prepared according to published procedures (Zingel et al, 1990;Leschke et al, 1995). Compounds 22, 23, and 40 were available by synthetic pathways reported for the synthesis of 19 to 21 (Elz et al, 2000).…”

Section: Methodsmentioning

confidence: 99%

Multiple Differences in Agonist and Antagonist Pharmacology between Human and Guinea Pig Histamine H₁-Receptor

Seifert¹,

Wenzel-Seifert²,

Bürckstümmer³

et al. 2003

J Pharmacol Exp Ther

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Species isoforms of histamine H 2 -, H 3 -, and H 4 -receptors differ in their pharmacological properties. The study aim was to dissect differences between the human H 1 R (hH 1 R) and guinea pig H 1 R (ghH 1 R). We coexpressed hH 1 R and gpH 1 R with regulators of G-protein signaling in Sf9 insect cells and analyzed the GTPase activity of G q -proteins. Small H 1 R agonists showed similar effects at hH 1 R and gpH 1 R, whereas bulkier 2-phenylhistamines and histaprodifens were up to ϳ10-fold more potent at gpH 1 R than at hH 1 R. Most 2-phenylhistamines and histaprodifens were more efficacious at gpH 1 R than at hH 1 R. Several first-generation H 1 R antagonists were ϳ2-fold, and arpromidine-type H 1 R antagonists up to ϳ10-fold more potent at gpH 1 R than at hH 1 R. [ The Phe-1533 Leu-153/Ile-4333 Val-433 double mutant expressed excellently but only partially changed the pharmacological properties of hH 1 R. Small H 1 R agonists and 2-phenylhistamines interacted differentially with human and guinea pig H 2 R in terms of potency and efficacy, respectively. Our data show the following: 1) there are differences in agonist-and antagonistpharmacology of hH 1 R and gpH 1 R encompassing diverse classes of bulky ligands. These differences may be explained by higher conformational flexibility of gpH 1 R relative to hH 1 R; 2) Phe-153 and Ile-433 are critical for proper folding and expression of hH 1 R; and 3) H 2 R species isoforms distinguish between H 1 R agonists.Histamine serves as a neurotransmitter and autacoid and acts through specific H x Rs designated as H 1 R, H 2 R, H 3 R, and H 4 R, respectively (Hill et al., 1997;Hough, 2001). The H 1 R couples to G q -proteins. Numerous H 1 R agonists and antagonists are known. H 1 R agonists are divided into three classes ( Fig. 1): 1) small agonists (2-4) derived from histamine (1), 2) histamine derivatives with bulkier aromatic substituents at position 2 of the imidazole ring (5-18), and 3) histaprodifens, e.g., compounds 19 to 23 Zingel et al., 1995;Elz et al., 2000). H 1 R agonists are important experimental tools to analyze H 1 R function in cellular and organ systems (Zingel et al., 1995;Hill et al., 1997). H 1 R antagonists are commonly divided into sedating (first-generation, 24-32) and nonsedating (second-generation, 41-45) antagonists (Fig. 2). Today, especially the second-generation H 1 R antagonists are of great importance for the treatment of allergic diseases (Hill et al., 1997). Guanidines 33, 34, and 36 to 39 derived from arpromidine (35) are dual H 2 R agonists/ H 1 R antagonists (Buschauer, 1989).The availability of H x R cDNAs allowed for the comparison of the pharmacological properties of H x R species isoforms in recombinant systems under identical experimental conditions. Such expression studies uncovered species differences This work was supported by the National Institutes of Health COBRE Award 1 P20 RR15563 and matching support from the State of Kansas and the University of Kansas (R.S.), a grant from the Army Research Office (DAAD 19-00-...

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“…Neomycin has been reported to inhibit hormone-stimulated IP 3 production through the blockade of PLC (Phillippe, 1994). The administration of U-73122 and neomycin dose-dependently prevented the hypernociception induced by 2-(3-trifluoromethylphenyl)-histamine (FMPH), a new, potent and selective H 1 -receptor agonist (Leschke et al, 1995). By contrast, U-73343, a succinimido analogue used as negative control for U-73122 being a weak inhibitor of PLC Smith et al, 1990), did not modify the hyperalgesia induced by FMPH.…”

Section: Discussionmentioning

confidence: 99%

“…The aim of the present study was to determine whether the stimulatory effect of H 1 -receptor agonists on PLC, and on DAG-and IP 3 -mediated intracellular pathways, participates in the mechanism of central hypernociception following activation of the H 1 -mediated histaminergic system. To this purpose, 2-(3-trifluoromethylphenyl)histamine (FMPH), a new, potent and selective H 1 -receptor agonist (Leschke et al, 1995) was employed.…”

Section: Introductionmentioning

confidence: 99%

H1-receptor stimulation induces hyperalgesia through activation of the phospholipase C-PKC pathway

Galeotti¹,

Malmberg-Aiello²,

Bartolini³

et al. 2004

Neuropharmacology

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The supraspinal cellular events involved in H 1 -mediated hyperalgesia were investigated in a condition of acute thermal pain by means of the mouse hot-plate test. I.c.v. administration of the phospholipase C (PLC) inhibitors U-73122 and neomycin antagonized the hyperalgesia induced by the selective H 1 agonist FMPH. By contrast, U-73343, an analogue of U-73122 used as negative control, was unable to modify the reduction of the pain threshold induced by FMPH. In mice undergoing treatment with LiCl, which impairs phosphatidylinositol synthesis, or treatment with heparin, an IP 3 -receptor antagonist, the hyperalgesia induced by the H 1 -receptor agonist remained unchanged. Similarly, pretreatment with D-myo inositol did not alter the H 1 -induced hypernociceptive response. Neither i.c.v. pretreatment with TMB-8, a blocker of Ca 2+ release from intracellular stores, nor pretreatment with thapsigargin, a depletor of Ca 2+ intracellular stores, prevented the decrease of pain threshold induced by FMPH. On the other hand, i.c.v. pretreatment with the selective protein kinase C (PKC) inhibitors calphostin C and chelerytrine resulted in a dose-dependent prevention of the H 1 -receptor agonist-induced hyperalgesia. The administration of PKC activators, such as PMA and PDBu, did not produce any effect on FMPH effect. The pharmacological treatments employed did not produce any behavioral impairment of mice as revealed by the rota-rod and hole-board tests. These results indicate a role for the PLC-PKC pathway in central H 1 -induced hyperalgesia in mice. Furthermore, activation of PLC-IP 3 did not appear to play a major role in the modulation of pain perception by H 1 -receptor agonists. #

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Synthesis and Histamine H1 Receptor Agonist Activity of a Series of 2-Phenylhistamines, 2-Heteroarylhistamines, and Analogs

Cited by 64 publications

References 23 publications

Interactions of Histamine H₁-Receptor Agonists and Antagonists with the Human Histamine H₄-Receptor

Interactions of Histamine H₁-Receptor Agonists and Antagonists with the Human Histamine H₄-Receptor

Multiple Differences in Agonist and Antagonist Pharmacology between Human and Guinea Pig Histamine H₁-Receptor

H1-receptor stimulation induces hyperalgesia through activation of the phospholipase C-PKC pathway

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Synthesis and Histamine H1 Receptor Agonist Activity of a Series of 2-Phenylhistamines, 2-Heteroarylhistamines, and Analogs

Cited by 64 publications

References 23 publications

Interactions of Histamine H1-Receptor Agonists and Antagonists with the Human Histamine H4-Receptor

Interactions of Histamine H1-Receptor Agonists and Antagonists with the Human Histamine H4-Receptor

Multiple Differences in Agonist and Antagonist Pharmacology between Human and Guinea Pig Histamine H1-Receptor

H1-receptor stimulation induces hyperalgesia through activation of the phospholipase C-PKC pathway

Contact Info

Product

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Interactions of Histamine H₁-Receptor Agonists and Antagonists with the Human Histamine H₄-Receptor

Interactions of Histamine H₁-Receptor Agonists and Antagonists with the Human Histamine H₄-Receptor

Multiple Differences in Agonist and Antagonist Pharmacology between Human and Guinea Pig Histamine H₁-Receptor