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W Schunack

Publications and source records attributed to W Schunack.

At least 127 records · Page 7Linked to original sources
PubMed1994

The H1 receptor agonist 2-(3-chlorophenyl)histamine activates Gi proteins in HL-60 cells through a mechanism that is independent of known histamine receptor subtypes.

In dibutyryl-cAMP-differentiated HL-60 cells, histamine H1 and formyl peptide receptors mediate increases in the cytosolic Ca2+ concentration ([Ca2+]i) via pertussis toxin-sensitive G proteins of the Gi family. We compared the effects of 2-(3-chlorophenyl)-histamine (CPH) [2-[2-(3-chlorophenyl)-1H-imidazol-4-yl] ethanamine], one of the most potent and selective H1 receptor agonists presently available, with those of histamine and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) in these cells. CPH increased [Ca2+]i through Ca2+ mobilization and Ca2+ influx. Unlike histamine-induced rises in [Ca2+]i, those induced by CPH were not desensitized in a homologous manner, and there was no cross-desensitization between CPH and histamine. Like fMLP, CPH activated phospholipases C and D, tyrosine phosphorylation, superoxide anion formation, and azurophilic granule release. The effects of CPH on [Ca2+]i, phospholipase D, and superoxide anion formation were inhibited by pertussis toxin. CPH and fMLP stimulated high affinity GTP hydrolysis by Gi proteins in HL-60 membranes. They also enhanced binding of guanosine-5'-O-(3-thio)triphosphate and GTP azidoanilide to, and cholera toxin-catalyzed ADP-ribosylation of, Gi protein alpha subunits. Histamine receptor antagonists did not inhibit the stimulatory effects of CPH, and CPH did not reduce fMLP binding in HL-60 membranes. Our data suggest that CPH activates Gi proteins in HL-60 cells through a receptor agonist-like mechanism that is, however, independent of known histamine receptor subtypes and formyl peptide receptors. CPH may be an agonist at an as yet unknown histamine receptor subtype or, by analogy with other cationic-amphiphilic substances, may activate G proteins directly. Future studies will have to take into consideration the fact that CPH, in addition to activating H1 receptors, may show other, most unexpected, stimulatory effects on G protein-mediated signal transduction processes.

Calcium↗
PubMed1994

[125I]iodoproxyfan, a new antagonist to label and visualize cerebral histamine H3 receptors.

Iodoproxyfan, i.e., 3-(1H-imidazol-4-yl)propyl-(4-iodophenyl)-methyl ether, is a novel potent and selective histamine H3 receptor antagonist. [125I]Iodoproxyfan binding to membranes of the rat striatum was reversible and saturable. Specific binding defined with 1 microM (R)-alpha-methylhistamine corresponded to 65% of the total at 30 pM. Scatchard analysis indicated a Kd of 65 pM and maximal binding capacity of 78 fmol/mg of protein. The specificity of [125I]Iodoproxyfan binding to H3 receptors was demonstrated by its pharmacological profile. A series of H3 receptor agonists inhibited [125I]iodoproxyfan binding with a similar maximal effect and with the expected order of potency and stereoselectivity ratio. H3 receptor antagonists inhibited the specific binding with the expected Ki values. In the presence of guanylnucleotides, 40% of sites exhibited a approximately 40-fold lower affinity for histamine, indicating that the H3 receptor belongs to the superfamily of G protein-coupled receptors and revealing the existence of two populations of sites. Well contrasted autoradiographic pictures of total [125I]iodoproxyfan binding to sections of the rat brain were obtained in a short time and over a low nonspecific binding. The heterogenous distribution of H3 receptors with high labeling of anterior cerebral cortex, ventral striatum and other limbic areas was confirmed. In addition, a clearly distinguishable laminated pattern of labeling was evidenced in the cerebral cortex and hippocampal formation. Hence, this new probe should be useful for sensitive assay and localization of the H3 receptor.

Animals↗
PubMed1993

Histamine analogues, XXXV: 2-substituted histamine derivatives containing classical moieties of H2-antagonists--a novel class of H1-agonists.

A new type of H1-agonists resulted from the combination of the essential histamine structure with parts of H2-antagonists. 2,4-Disubstituted imidazole derivatives were synthesized by reaction of imidic acid methyl esters with 1,3-dihydroxypropanone, 1,4-dihydroxybutanone or 2-oxo-4-phthalimido-1-butylacetate in liquid NH3. The imidazole intermediates were converted into histamine analogues by simple deprotection, Gabriel synthesis followed by deprotection, or by side-chain elongation via the nitriles and final hydrogenation. The new compounds were screened for H1-activity on the isolated guinea-pig ileum and for H2-antagonistic activity on the isolated guinea-pig right atrium. The substances are comparably weak H1-agonists and moderate H2-blockers.

Animals↗
PubMed1993

G protein-linked receptors labeled by [3H]histamine in guinea pig cerebral cortex. I. Pharmacological characterization [corrected].

Binding of histamine to washed membranes from guinea pig cerebral cortex can be described empirically as two classes of distinct and independent sites (log IP1 = -8.45 +/- 0.02, R1;t = 98 +/- 6 pmol/g of protein; log KP2 = -6.34 +/- 0.22, R2.t = 990 +/- 60 pmol/g of protein). At 1.4 nm [3H]histamine, the kinetics of association and dissociation are biexponential. The values of k-Pj/k+Pj calculated for parallel one-step processes agree well with the corresponding values of KPj. Both k-p1 and k-P2 are increased by 0.1 mM guanylylimidodiphosphate; apparent capacity at equilibrium is reduced for both classes of sites, with little or no change in KP1 or KP2. Twenty-six H2 and H3 agonists and antagonists block access of [3H]histamine to the same sites, and the binding patterns reveal either one or two hyperbolic terms [i.e., sigma nj = 1 F' jKj/(Kj+[L])]. Two terms are required for six agonists and six antagonists, and F'2 varies widely from ligand to ligand. Also, the quantity log (K2/K1) is correlated with F'1 among agonists but with F'2 among antagonists (K1 < K2). The pharmacological selectivity is suggestive of both H2 and H3 receptors. An H2 specificity emerges from the appropriate values of Kj for 12 H2 agonists (i.e., K1 when n = 1 and K2 when n = 2; p = 0.00045), although a specificity distinct from that of H2 receptors is found with H2 antagonists. An H3 specificity emerges from the inhibitory potencies (IC50) of eight H3 agonists (p = 0.00025) and eight H3 antagonists (p = 0.0019); also, the sites labeled by [3H]histamine resemble H3 receptors reportedly labeled by N alpha-[3H]methylhistamine and (R)-alpha-[3H]methylhistamine. Ligand-dependent differences in F'2 are inconsistent with the notion of distinct and independent sites, and the tendency of antagonists to promote the sites of weaker affinity (F'2) argues against a ligand-regulated equilibrium between two states. The physical significance of the binding parameters is therefore unclear. The failure to identify an unambiguous pharmacological specificity may reflect the failure to assess binding in the correct mechanistic context.

Animals↗
PubMed1992

Synthesis, absolute configuration, stereoselectivity, and receptor selectivity of (alpha R, beta S)-alpha,beta-dimethylhistamine, a novel high potent histamine H3 receptor agonist.

Depending on the selected synthetic pathway, structural variations of the neurotransmitter histamine led to mixtures of alpha,beta-dimethylhistamines as well as to the corresponding pure optical isomers. One of these isomers, namely (alpha R,beta S)-alpha,beta-dimethylhistamine, proved to be a highly potent H3 receptor agonist with exceptional receptor selectivity. The absolute configuration of the compound was determined by X-ray structure analysis of its dihydrobromide using the anomalous dispersion of bromine. The optical purity of both enantiomers of erythro-alpha,beta-dimethylhistamine was checked by 1HNMR investigations after acylation of the amines with (R)-2-methoxy-2-phenylacetyl chloride. As expected H3 receptors distinguish in a very strong way between the title compound and its alpha S,beta R-configured enantiomer. The agonistic potency of the latter is 2 orders of magnitude lower than the potency of (alpha R,beta S)-alpha,beta-dimethylhistamine.

Animals↗
PubMed1992

Histamine H1 receptors mediate vasodilation in guinea-pig ileum resistance vessels: characterization with computer-assisted videomicroscopy and new selective agonists.

Histamine receptors on guinea-pig ileum submucosal arterioles (outside diameter 40-80 microns) were studied in vitro using a computer-assisted videomicroscopy system (Diamtrak). Histamine receptor agonists investigated in this study were histamine, the H1 receptor-selective compound, 2-[2-(3-fluorophenyl)-4-imidazolyl]ethanamine (VZ 20), the H2 receptor-selective compounds, dimaprit, impromidine, (+/-)-N1-[3-(4-fluorophenyl)-3-(pyridin-2-yl)propyl]- N2-[3-(1H-imidazol-4-yl)propyl]guanidine (arpromidine) and (+/-)-N1-[3-(3,4-difluorophenyl)-3-(pyridin-2-yl)propyl]- N2-[3-(1H-imidazol-4-yl)propyl]guanidine (BU-E-75), as well as the H3 receptor-selective drug, (R)-alpha-methylhistamine ((R)-alpha-MeHA). Applied to vessels at resting tone, the agonists (1 nM-300 microM) did not change arteriolar diameter. Vessels preconstricted by 10 microM noradrenaline showed similar concentration-dependent vasodilations with histamine and VZ 20 (pD2 = 5.38 and 5.36, respectively). This histamine-induced vasodilation was not affected by tetrodotoxin (0.5 microM) or indomethacin (1 microM), but was completely abolished in the presence of 1 microM of the H1 receptor antagonist, mepyramine. Calculation of the antagonist affinity of mepyramine for the histamine receptors in submucosal arterioles yielded a pA2 of 9.46. In contrast to histamine and VZ 20, the H2 receptor agonist, dimaprit, and the H3 receptor agonist, (R)-alpha-MeHA, were ineffective at preconstricted arterioles. The guanidine-type H2 receptor agonists, impromidine, apromidine and BU-E-75, produced vasodilation at noradrenaline-preconstricted arterioles (-log EC50 = 4.47, 5.30 and 5.39, respectively) but, in contrast to histamine, were ineffective at arterioles preconstricted by U-46619 (300 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Iodoaminopotentidine and related compounds: a new class of ligands with high affinity and selectivity for the histamine H2 receptor.

The synthesis and biological evaluation of a new class of histamine H2 antagonists with N-cyano-N'-[omega-[3-(1-piperidinylmethyl)phenoxy] alkyl]guanidine partial structure are described as part of an extensive research program to find model compounds for the development of new radioligands with high H2 affinity and specific activity. High receptor affinity is achieved by an additional (substituted) aromatic ring, which is connected with the third guanidine N by a carbon chain spacer and an amine, carboxamide, ester, or sulfonamide link ("polar group"). In functional studies for H2 antagonistic activity and other pharmacological actions [e.g. H1 antihistaminic, antimuscarinic, antiadrenergic (alpha 1, beta 1), 5-HT2 blocking activity] in the isolated guinea pig atrium and ileum and rat aorta and tail artery, the compounds proved to be highly potent and selective histamine H2 receptor antagonists. The H2 antagonistic activity is mainly depending on the length of both the N'-alkyl chain (chain A) and the N"-spacer (chain B). Compounds with a C3 chain A and a C2 chain B are most potent in the preferred group of substances, i.e., the carboxamide series. A wide variety of substituents at the aromatic ring is tolerated, among them iodine, amino, and azido groups. These compounds are up to 32 times more potent than cimetidine in the isolated guinea pig right atrium. The replacement of the carboxamide by an ester group (44c) is well tolerated, while replacement of the cyanoguanidine by an urea group results in nearly 100-fold decrease in activity (46c,e). The iodinated benzamides are among the most potent H2 antagonists known so far. The [125I]-labeled form of 31f ([125I]iodoaminopotentidine, [125I]-N-[2-(4-amino-3-iodobenzamido) ethyl]-N'-cyano-N"-[3-[3-(1-piperidinylmethyl) phenoxy]propyl]guanidine) and its photolabile analogue 31h ([125I]iodoazidopotentidine, [125I]-N-[2-(4-azido-3- iodobenzamido)ethyl]-N'-cyano-N"-[3-[3-(1-piperidinyl-methyl)pheno xy] propyl]guanidine) proved to be useful probes for reversible and irreversible labeling of the histamine H2 receptor. Radioligand binding studies in guinea pig cerebral membranes revealed considerably higher H2 receptor affinity for 31f (pKi = 9.15), 31h (pKi = 8.58), and some analogues than functional experiments (guinea pig atrium), presumably reflecting an easier access to the H2 receptors in membranes.

Aniline Compounds↗
PubMed1992

The effect of lipophilic substituents on the H2-histaminergic activity of some close analogues of impromidine.

The cimetidine-like moiety of the potent H2-agonist impromidine (9a) and three closely related guanidines (10a, 11a, and 12a) which are modified in the imidazolylpropyl portion, has been replaced by 2-[(2-pyridyl)methylthio]ethyl, 2-(benzylthio)ethyl and 3,3-diphenylpropyl substituents. Guanidines 10-12 were obtained from acidic hydrolysis of corresponding N-benzoyl guanidines 7, 8, and 15, accessible by successive aminolysis of diphenyl N-benzoyl carbonimidate (2) according to known methods. Compared with leads 10a and 11a lipophilic substitution affords almost equipotent H2-agonists 10b-d and 11b-d, while substituents with increasing lipophilicity enhance both intrinsic activity and potency of the weak partial agonist 12a at guinea-pig atrial H2-receptors. Guanidines 10-12 are weak H1-antagonists on the isolated guinea-pig ileum.

Animals↗
PubMed1992

Modulation of IgE-mediated histamine release from human leukocytes by a new class of histamine H2-agonists.

A new class of phenyl (pyridylalcyl) guanidines, acting as potent histamine H2-agonists, inhibits IgE-mediated human basophil histamine release in a nanomolar range. IC30-level of three substitutes of this group (arpromidine, BUA-75, and FRA-19) were found to be 0.02, 0.015 and 0.008 microM. The inhibition appeared with a fast onset (plateau after 10 min. preincubation) and claimed its maximum (60 +/- 2.9%, 63 +/- 1.8%, and 61 +/- 3.1%, n = 7) with 10 microM of the compounds. H2-mediated inhibition was totally blocked by 10 microM famotidine, a potent histamine H2-antagonist. The amount of anti-IgE or antigen for the initiation of the immunological release influenced the strength of inhibition of H2-agonist FRA-19 (p less than 0.05). Combined preincubation of FRA-19 with zardaverine, a cAMP-specific phosphodiesterase III/IV inhibitor, produced a synergistical inhibitory effect of leukocyte histamine release, which might explained by their different sites of action on intracellular cAMP levels. The capability of histamine to inhibit its own release is mediated by H2-receptors exclusively. New, potent H2-receptor stimulating compounds with positive inotropic effects possess additional potent anti-allergic properties.

Basophils↗
PubMed1992

Synthesis and histamine H2-receptor activity of heterocyclic impromidine analogues.

Analogues of the H2-agonist impromidine with unsubstituted or substituted aromatic or non-aromatic heterocycles instead of the 5-methylimidazole group were prepared via the benzoylguanidine method and tested for H2-agonistic and H1-antagonistic activity in the guinea-pig isolated right atrium and ileum, respectively. Compounds with unsubstituted 2- or 3-pyridyl, 2-pyrazinyl, or 5-pyrimidyl thioether portion proved to be about equipotent in the atrium (about 2-4x histamine). Highest potency was found in the 5-chloro-3-pyridylthioethylguanidine 8h, that is about 20 times more potent as an H2-agonist than histamine, corresponding to about 8 times the activity of the unsubstituted parent compound 8g. It is demonstrated by the piperidinyl- and morpholinylalkyl guanidines 8m-o that an aromatic ring is not required in the affinity-conferring moiety of H2-agonists (8n: 1.3x histamine). Replacement of the (5-methylimidazol-4-yl)methylthio group in the H2-antagonist cimetidine by halogenated pyridyl, pyrazinyl and pyrimidinyl thioethers resulted in compounds inactive as H2-antagonists, giving further evidence for differences in the structural requirements of the affinity-conferring portions of H2-agonists and antagonists and their mode of interaction with the receptor protein.

Animals↗
PubMed1992

Histamine increases cytosolic Ca2+ in dibutyryl-cAMP-differentiated HL-60 cells via H1 receptors and is an incomplete secretagogue.

Human neutrophils and dibutyryl-cAMP (Bt2cAMP)-differentiated HL-60 cells possess receptors for the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMet-Leu-Phe), which mediate activation of phospholipase C, with subsequent increase in cytosolic Ca2+ concentration ([Ca2+]i) and activation of specific cell functions. In many cell types, histamine, via H1 receptors, activates phospholipase C, but it is unknown whether neutrophilic cells possess functional H1 receptors. We compared the effects of histamine with those of fMet-Leu-Phe on activation of these cells. In Bt2cAMP-differentiated HL-60 cells, substances increased [Ca2+]i in the effectiveness order fMet-Leu-Phe greater than histamine greater than betahistine. Pertussis toxin diminished fMet-Leu-Phe-induced rises in [Ca2+]i to a greater extent than those induced by histamine. H1 but not H2 antagonists inhibited histamine- and betahistine-induced rises in [Ca2+]i. fMet-Leu-Phe and histamine activated phospholipase C and increased [Ca2+]i through release of Ca2+ from intracellular stores and sustained influx of Ca2+ from the extracellular space. The substances also induced Mn2+ influx. Ca2+ and Mn2+ influxes were inhibited by 1-(beta-[3-(4-methoxyphenyl)propoxyl]-4-methoxyphenethyl)-1H-imida zole hydrochloride (SK&F 96365). The stimulatory effects of histamine on [Ca2+]i were more sensitive to inhibition by 4 beta-phorbol 12-myristate 13-acetate than were those of fMet-Leu-Phe. Unlike fMet-Leu-Phe, histamine did not activate superoxide anion formation, release of beta-glucuronidase, and tyrosine phosphorylation. In neutrophils, histamine and betahistine did not induce rises in [Ca2+]i. Our data show that (i) in Bt2cAMP-differentiated HL-60 cells, histamine increases [Ca2+]i via H1 receptors coupled to pertussis toxin-sensitive and possibly, pertussis toxin-insensitive heterotrimeric regulatory guanine nucleotide-binding proteins, (ii) histamine activates nonselective cation channels, and (iii) unlike fMet-Leu-Phe, histamine is an incomplete secretagogue.

Betahistine↗
PubMed1992

Inhibition of IgE-mediated histamine release from human peripheral leukocytes by selective phosphodiesterase inhibitors.

Several phosphodiesterase (PDE) inhibitors with the capacity to inhibit the PDE IV isoenzyme produce dose-dependent inhibition of IgE-mediated histamine release (HR) from human peripheral leukocytes in vitro. Inhibition reached a maximum after 20 min of preincubation (IC30: 6-30 microM, IC50: 30-80 microM). Motapizone--a potent inhibitor of the isoenzyme PDE III--was much less effective, thus giving indirect evidence that PDE IV plays a predominant role in the control of cAMP cleavage in human basophils. The inhibiting effect of PDE-III/IV-selective compounds on IgE-mediated HR did not exceed the action of PDE-IV-selective inhibitors. The inhibition of anti-IgE-induced HR by zardaverine (a PDE-III/IV-inhibiting compound) was synergistically enhanced in the combined presence of forskolin or the recently synthesized histamine H2-agonist FRA 19).

Basophils↗
PubMed1992

Histamine analogues. 36th communication. Basically substituted histamine derivatives with H1-agonistic activity.

Piperidinoalkyl-, morpholinoalkyl- or [(pyrid-2-yl)methylthio]alkyl-substituents were introduced into position 2 of the essential histamine structure. These 2-substituted histamine derivatives were prepared via reaction of imidate hydrochlorides in liquid ammonia under pressure with 1,3-dihydroxypropanone followed by a stepwise build-up of the side chain in position 4 of the imidazole nucleus (route I) or by cyclization with 2-oxo-4-phthalimido-1-butyl acetate (route II) followed by deprotection of the primary amine function. The novel compounds were screened for H1-activity on the isolated guinea-pig ileum and for H2-activity on the isolated guinea-pig right atrium. While 10a, c-e proved to be weak partial H1-agonists, 10b, f were very weak H1-antagonists.

Animals↗
PubMed1991

[Quinazolinones. 18. Synthesis and H1/H2-antihistaminic action of omega-[2-aryl-2,3-dihydro-4(1H)-quinazolinone-1-yl]alkyl substituted ureas and cyanoguanidines].

A series of (2-aryl-2,3-dihydro-4(1H)-quinazolinon-1-yl)alkyl-substituted cyanoguanidines and ureas with histamine, cimetidine or roxatidine partial structure was prepared and tested for H1- and H2-antagonism at the isolated ileum and the isolated right atrium of the guinea-pig. All compounds investigated were only very weak H1-antagonists, whereas the 3-[3-(1-piperidinyl-methyl)phenoxy]propyl-cyanoguanidines and -ureas were more potent H2-antagonists than cimetidine, maximally achieving about ranitidine's potency.

Animals↗
PubMed1991

Novel chiral H3-receptor agonists.

Several alkyl-substituted histamine derivatives have been synthesized and investigated for their agonistic potency on three classes of histamine receptors. While all investigated compounds are full agonists at H3-receptors their relative potency vs. histamine is strongly varying and culminates in alpha R, beta S-dimethylhistamine which is a highly potent and selective H3-receptor agonist.

Animals↗
PubMed1991

The histamine H3-receptor: pharmacology, roles and clinical implications studied with agonists.

Among a series of methylated histamine derivatives, (R) alpha, (S) beta,-dimethylhistamine has been identified as a novel potent and selective H3-receptor agonist, even slightly more potent than (R) alpha-methylhistamine and displaying similar properties in vivo. Several studies suggesting that (R) alpha-methylhistamine might find various clinical applications, it was submitted to toxicological studies and initial clinical trials. The drug seems to display a very low animal toxicity, and, in humans, is well absorbed orally and metabolized via ring methylation before urinary excretion.

Animals↗