Inhibition of electrically evoked contractions of guinea-pig ileum preparations mediated by the histamine H3 receptor

Menkveld, Gerda J.; Timmerman, H.

doi:10.1016/0014-2999(90)90458-i

Cited by 45 publications

(26 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also in the GPI, the Schild analysis was consistent with competitive blockade of (R)-␣-methylhistamine by SCH 79687 and thioperamide at the concentrations tested. The estimated pA 2 for thioperamide against (R)-␣-methylhistamine is similar to previous H 3 receptor pA 2 estimates reported for this compound in GPI (Menkveld and Timmerman 1990;Rizzo et al, 1995). Together, these findings confirm that SCH 79687 is a functional histamine H 3 receptor antagonist in vitro.…”

Section: Discussionsupporting

confidence: 79%

Pharmacological Characterization of the Novel Histamine H₃-Receptor Antagonist N-(3,5-Dichlorophenyl)-N′-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687)

McLeod¹,

Rizzo²,

West³

et al. 2003

J Pharmacol Exp Ther

View full text Add to dashboard Cite

We present the pharmacological and pharmacokinetic profiles of a novel histamine H 3 receptor antagonist, N- (3,phenyl]-methyl]-urea (SCH 79687). The H 3 -receptor binding K i values for SCH 79687 were 1.9 and 13 nM in the rat and guinea pig (GP), respectively. The K i values for SCH 79687 at histamine H 1 and H 2 receptors were greater than 1 M. SCH 79687 showed a 41-and 82-fold binding selectivity for the H 3 receptor over ␣ 2A -adrenoceptors and imidazoline I 2 , and Ͼ500-fold H 3 selectivity compared with over 60 additional receptors. The pA 2 value for SCH 79687 in the GP ileum electrical field-stimulated (EFS) contraction was 9.6 Ϯ 0.3. Similar H 3 antagonist activity was observed in the EFS cryopreserved and fresh tissue isolated human saphenous vein (HSV) assays (pK b ϭ 9.4 Ϯ 0.3 and 10.1 Ϯ 0.4). SCH 79687 (30 nM) did not block clonidine-induced inhibition of EFSinduced contractions in HSV. SCH 79687 (ED 50 ϭ 0.3 mg/kg i.v.) attenuated (R)-␣-methylhistamine inhibition of sympathetic hypertensive responses in the GP. At the time of activity evaluation, the GP plasma SCH 79687 concentration was 25 ng/ml at the dose of 0.3 mg/kg i.v. In feline nasal studies, combined administration of SCH 79687 (3 mg/kg i.v.) and the H 1 -antagonist loratadine (3 mg/kg i.v.), at individual doses that do not produce decongestion, inhibited the compound 48/80-induced congestion by 47%. The ␣-adrenergic agonist phenylpropanolamine (PPA; 1 mg/kg i.v.) also attenuated compound 48/80 nasal responses by 42%. Unlike the H 3 /H 1 combination that did not affect blood pressure (BP), PPA (1 mg/kg i.v.) significantly increased BP compared with control animals by a maximum of 31 mm Hg. Orally, SCH 79687 (10 mg/kg) plus loratadine (10 mg/kg) also produced decongestion without effects on BP. In pharmacokinetic studies, oral dosing with SCH 79687 in the rat (10 mg/kg) and monkey (3 mg/kg) achieved plasma C max and area under the curve values greater than 1.5 and 12.1 g ⅐ h/ml, respectively. SCH 79687 is an orally active H 3 antagonist with a good pharmacokinetic profile that, in combination with an H 1 antagonist, demonstrates decongestant efficacy comparable with oral sympathomimetic decongestants but without hypertensive liabilities.

show abstract

Section: Discussionsupporting

confidence: 79%

Pharmacological Characterization of the Novel Histamine H₃-Receptor Antagonist N-(3,5-Dichlorophenyl)-N′-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687)

McLeod¹,

Rizzo²,

West³

et al. 2003

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…(4) The present cytochrome P450 type II coordination potencies for thioperamide, clobenpropit and ciproxifan are in the sub-to low-micromolar range. In contrast, these compounds exhibit in vitro H 3 receptor antagonist pK i and pA 2 in the sub-to low-nanomolar range [3,9,11], suggesting 2-3 orders of magnitude selectivity for H 3 receptors over adrenal P450 enzymes. However, the intravenous and oral thioperamide, clobenpropit and ciproxifan doses used to inhibit H 3 receptor activation in vivo are reported in the range of 0.2-3 mg/kg [5,8,[27][28][29] indicating that the in vivo safety margin relative to adrenal steroidogenesis is closer to one order of magnitude.…”

Section: Discussionmentioning

confidence: 97%

“…The histamine H 3 receptor inhibits histaminergic [1], parasympathetic [2,3] and sympathetic [4][5][6][7][8][9] neuron function in a variety of species. This activity has stimulated discovery efforts to develop potent and selective histamine H 3 receptor ligands that may have therapeutic utility.…”

Section: Introductionmentioning

confidence: 99%

Coordination of Histamine H<sub>3</sub> Receptor Antagonists with Human Adrenal Cytochrome P450 Enzymes

Yang¹,

Hey²,

Aslanian³

et al. 2002

Pharmacology

View full text Add to dashboard Cite

Optical difference spectroscopy was used to identify and quantify human adrenal microsomal and mitochondrial cytochrome P450 enzyme interactions with the histamine H₃ receptor antagonists thioperamide, clobenpropit and ciproxifan. Addition of these structurally diverse imidazole H₃ receptor antagonists to cytochrome-P450-containing human adrenal microsomal and mitochondrial preparations resulted in concentration-dependent type II optical difference spectra. Respective spectral dissociation constants (K_S) for the drug interactions with human adrenal microsomal and mitochondrial cytochrome P450 were 1.5 and 1.6 µmol/l for thioperamide, 3.1 and 0.28 µmol/l for clobenpropit and 0.10 and 0.11 µmol/l for ciproxifan. The three compounds demonstrated a similar activity profile in cytochrome-P450-containing bovine adrenal microsomal and mitochondrial preparations. Findings indicate direct coordination of these imidazole-containing H₃ receptor antagonists with the heme moiety of human adrenal cytochrome P450 isozymes.

show abstract

“…However, histamine receptors which mediate inhibition of both cholinergic (Fialland, 1979) and NANC (Ambache et al, 1973) contractions within this preparation have also been suggested: on the basis of pharmacological data it was proposed that these effects were mediated by (Menkveld & Timmerman, 1990). The atropine-resistant response evoked by electric field stimulation of the guinea-pig isolated ileum preparation in this study comprised an initial fast contraction and a second slow contraction.…”

Section: Discussionmentioning

confidence: 99%

Characterization of histamine‐H₃ receptors controlling non‐adrenergic non‐cholinergic contractions of the guinea‐pig isolated ileum

Taylor¹,

Kilpatrick²

1992

British J Pharmacology

View full text Add to dashboard Cite

1 In the presence of atropine, mepyramine and ranitidine, electric field stimulation of the guinea-pig isolated ileum longitudinal muscle-myenteric plexus preparation resulted in a two component nonadrenergic non-cholinergic contraction. The initial contraction had a duration of approximately 1 s whereas the second contraction lasted approximately 10 s. The second contraction was completely inhibited by tetrodotoxin (0.2 x 10-6M) with minimal effect on the initial contraction. Phentolamine (3 x 10-6M), propranolol (3 x 10-6M) and hexamethonium (10-kM), did not significantly reduce either component of the contractile response. 2 The neurokinin NK1 receptor antagonists, GR82334 and GR71251, produced concentration-related (EC50 = 564 and 173nm respectively) inhibitions of the second contraction with no effect on the initial contraction. The neurokinin NK2 receptor antagonists MEN 10207 and Ac-Leu-Asp-Gln-Trp-Phe-Gly-NH2 (R 396), 1 x 10-i9-0-5M, were without effect on either component of the contractile response. 3 Concentration-related inhibitions of the second contraction, with no effect on the initial contraction, were observed after inclusion of the histamine H3 receptor agonists (R)a-methylhistamine (pD2 = 7.6), Ni-methylhistamine (pD2 = 7.7) and N',N"-dimethylhistamine (pD2 = 6.3). Histamine also inhibited the second contraction (pD2 = 6.2) in a concentration-related manner but produced a lower maximum inhibitory effect than the other agonists tested. 4 Inclusion of the H3 receptor antagonists, thioperamide, burimamide, impromidine and phenylbutanoylhistamine, caused parallel concentration-related rightward shifts in the concentration-response curve to (R)-a-methylhistamine. In each case, Schild analysis of these data gave slopes not significantly different from unity. Antagonist affinity values for thioperamide (pA2 = 8.2), burimamide (pA2 = 7.0) and impromidine (pA2 = 7.0) were consistent with values obtained in other assays of the H3 receptor. However, phenylbutanoylhistamine (pA2 = 5.8) and betahistine (pKB < 4) had affinities more than ten fold lower than values obtained in other assays of the H3 receptor. 5 Exposure of the tissues to N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (10-6 M) for 7-30min followed by extensive washing, had no effect on basal contractions, but produced a rightward shift in the concentration-response curves to (R-a-methylhistamine, N"-methylhistamine, N",Nl-dimethylhistamine and histamine. This treatment also resulted in a decrease in the maximum inhibitory response obtainable. Apparent agonist affinity (pKD) values of 7.01, 7.06, 6.09 and 6.13 were estimated for (R)-x-methylhistamine, Nl-methylhistamine, N',N"-dimethylhistamine and histamine respectively. 6 In conclusion, pharmacological analysis has revealed that histamine H3 receptors in the guinea-pig ileum modulate the release of non-adrenergic non-cholinergic neurotransmitters, one of which is probably substance P. In addition we have identified N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline as an irreversible antagonist ...

show abstract

Inhibition of electrically evoked contractions of guinea-pig ileum preparations mediated by the histamine H3 receptor

Cited by 45 publications

References 9 publications

Pharmacological Characterization of the Novel Histamine H₃-Receptor Antagonist N-(3,5-Dichlorophenyl)-N′-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687)

Pharmacological Characterization of the Novel Histamine H₃-Receptor Antagonist N-(3,5-Dichlorophenyl)-N′-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687)

Coordination of Histamine H<sub>3</sub> Receptor Antagonists with Human Adrenal Cytochrome P450 Enzymes

Characterization of histamine‐H₃ receptors controlling non‐adrenergic non‐cholinergic contractions of the guinea‐pig isolated ileum

Contact Info

Product

Resources

About

Inhibition of electrically evoked contractions of guinea-pig ileum preparations mediated by the histamine H3 receptor

Cited by 45 publications

References 9 publications

Pharmacological Characterization of the Novel Histamine H3-Receptor Antagonist N-(3,5-Dichlorophenyl)-N′-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687)

Pharmacological Characterization of the Novel Histamine H3-Receptor Antagonist N-(3,5-Dichlorophenyl)-N′-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687)

Coordination of Histamine H<sub>3</sub> Receptor Antagonists with Human Adrenal Cytochrome P450 Enzymes

Characterization of histamine‐H3 receptors controlling non‐adrenergic non‐cholinergic contractions of the guinea‐pig isolated ileum

Contact Info

Product

Resources

About

Pharmacological Characterization of the Novel Histamine H₃-Receptor Antagonist N-(3,5-Dichlorophenyl)-N′-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687)

Pharmacological Characterization of the Novel Histamine H₃-Receptor Antagonist N-(3,5-Dichlorophenyl)-N′-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687)

Characterization of histamine‐H₃ receptors controlling non‐adrenergic non‐cholinergic contractions of the guinea‐pig isolated ileum