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W Schunack

Publications and source records attributed to W Schunack.

At least 91 records · Page 5Linked to original sources
PubMed1997

Binding of histamine H3-receptor antagonists to hematopoietic progenitor cells. Evidence for a histamine transporter unrelated to histamine H3 receptors.

Hematopoietic progenitor cells can take up histamine or release IL-3-induced histamine through a bi-directional transport system that is blocked by H3-receptor antagonists. In the present study we demonstrate a correlation between the affinity of various H3-receptor antagonists and their potency as inhibitors of histamine uptake. All compounds that blocked histamine uptake also inhibited IL-3-induced histamine release. Yet, classical H3 receptors are not involved in this biological activity, since highly specific histamine H3-receptor agonists neither alter histamine uptake nor affect the release of endogenous histamine synthesized in response to IL-3. Furthermore, the inhibitory effect of H3-receptor antagonists on histamine uptake was not reversed by the agonists. Unlike H3-receptor antagonists, the agonists did not displace the binding of the labeled antagonist iodoproxyfan.

Animals↗
PubMed1997

Pharmacological properties of cardiovascular histamine H1 receptor binding sites: characterisation with 2-phenylhistamines.

We determined and compared the molecular properties of histamine H1 receptor binding sites in bovine thoracic aorta smooth muscle and guinea pig myocardial membranes from ventricles with saturation and inhibition binding assay, using 3H-mepyramine to label the receptor and specific and selective H1 receptor agonists of the 2-phenylhistamine group as displacers of specific 3H-mepyramine binding. 3H-mepyramine binds in a saturable manner to a homogenous population of binding sites with a K(D) of 5.6 nM and a Bmax of 57 fmol/mg of protein in bovine aorta vascular smooth muscle membranes, whereas in the guinea pig myocardium high and low affinity 3H-mepyramine binding sites exist having the following molecular characteristics: a K(D) of 1.6 nM and a Bmax of 99 fmol/mg of protein (high affinity site) and a K(D) 15.0 nM and a Bmax of 466 fmol/mg of protein (low affinity site). Halogenated 2-phenylhistamines: 2-(3-fluoro-) (2-FPH), 2-(3-trifluoromethyl-) (2-triFMPH), 2-(3-chloro-) (2-CPH), 2-(3-bromo-) (2-BPH) and 2-(3-iodophenyl)histamine (2-IPH), which showed high selectivity and potency for H1 receptors in the functional pharmacological studies, were potent inhibitors of specific radioligand binding in comparison with histamine and parent nonhalogenated 2-phenylhistamine (2-PH). Their rank order of potencies and affinities differ significantly for the vascular and cardiac H1 receptor binding sites: Specific 3H-mepyramine binding to H1 receptors in bovine vascular smooth muscle membranes was displaced in a biphasic manner by 2-(3-fluoro-), 2-(3-trifluoromethyl-), 2-(3-chloro-), 2-(3-bromo-), 2-(3-iodophenyl)histamine and histamine. In guinea pig ventricular myocardium the rank order was 2-(3-iodo-), 2-(3-bromo-), histamine, 2-(3-chloro-), and 2-(3-fluorophenyl)histamine showing better correlation with the lipophilicity of the derivatives than in vascular tissue (order of lipophilicity: 2-triFMPH >2-IPH >2-BPH >2-CPH >2-FPH >>2-PH). Displacement of the radioligand binding to myocardial H1 receptor by the above drugs is (except for 2-(3-fluorophenyl)histamine), better fitted to a two-site model. 2-phenylhistamine, which acted as a moderate agonist in functional studies, displaced the radioligand in a monophasic manner and was the weakest displacer of specific radioligand binding in both model systems (pKi = 5.76--vascular and 5.57--cardiac tissue). The agonistic nature of the halogenated 2-phenylhistamine derivatives was confirmed on the molecular level, since their interaction with the H1 receptor is regulated by guanine nucleotides. GTP (0.1 mM) significantly lowered the affinities of all tested halogenated 2-phenylhistamines and histamine for H1 receptor binding site converting biphasic displacement curves, to monophasic ones, whereas GTP had no effect on the affinity of 2-PH. The results of this study support the conclusions that bovine vascular and guinea pig myocardial histamine H1 receptors differ in their molecular properties. Selective and potent H1 receptor agonists of 2-phenylhistamine class can discriminate between vascular and cardiac receptor.

Animals↗
PubMed1997

Bioavailability, antinociceptive and antiinflammatory properties of BP 2-94, a histamine H3 receptor agonist prodrug.

(R)alpha-Methylhistamine [(R)alpha-MeHA], a potent and selective histamine H3 receptor agonist in vitro and in vivo in rodents, was found to display comparatively low plasma level in healthy human volunteers, attributable to an extensive methylation of the drug's imidazole ring by histamine-N-methyltransferase. To limit this inactivation process, BP 2-94, ie., (R)-(-)-2-[[N-[1-(1H-imidazol-4-yl)-2-propyl]imino]phenylmethyl] phenol, was selected as a prodrug. A sensitive radioimmunoassay was developed to study the generation of (R)alpha-MeHA slowly released from BP 2-94 in vitro and in vivo by chemical hydrolysis. In mice after oral administration of BP 2-94 high levels of both prodrug and (R)alpha-MeHA were detected in plasma and various tissues except in the brain. In humans receiving 0.1 mmol BP 2-94 orally, plasma levels of (R)alpha-MeHA-like immunoreactivity decayed with a t(1/2) more than 24 hr, the area under the curve being two orders of magnitude higher than after oral administration of (R)alpha-MeHA. BP 2-94 displayed antiinflammatory and antinociceptive properties in rodents, related to the H3 receptor stimulation. It dose-dependently inhibited capsaicin-induced plasma protein extravasation in many rat tissues with ED50s of 0.6 to 14 micromol/kg p.o., and maximal reductions by 35 to 87%. BP 2-94 also reduced zymosan-induced paw swelling in mice with an ED50 of 1 micromol/kg p.o. and showed marked activity in the phenylbenzoquinone-induced writhing (ED50 = 0.03 micromol/kg, p.o.) or formalin tests in mice, but not in the hot plate jump test. From its pharmacokinetics and pharmacological profile BP 2-94 appears to be a promising novel therapeutic agent in disorders such as asthma, migraine or a variety of inflammatory diseases and pain associated with these disorders.

Adult↗
PubMed1997

Search for novel leads for histamine H3-receptor antagonists: amine derivatives.

In search for novel leads for histamine H3-receptor antagonists a number of amine derivatives of different (1 H-imidazol-4-yl)anilines and omega-(1 H-imidazol-4-yl)alkanamines were prepared. Pharmacological in vitro H3-receptor investigations of the prepared urea, amide, inverse amide, thioamide, and thiourea derivatives on synaptosomes of rat cerebral cortex proved that the aniline derivatives are inactive at H3-receptors, whereas derivatives of the omega-(1 H-imidazol-4-yl)-alkanamines showed moderate to good activity. Some compounds are active in the nanomolar concentration range. The most potent compounds in this series are the thioamide derivative 7 and the urea derivatives 11, 12 of 3-(1 H-imidazol-4-yl) propanamine. Therefore, the urea derivatives were tested in vitro on isolated organs of the guinea pig for their activity on the other two histamine receptor subtypes proving their high selectivity. In vivo studies of the effects of the urea derivatives 11 and 12 on brain Nt-methylhistamine levels, a test of central H3-receptor activity after peroral application to mice, showed no detectable activity. Thus, the urea type antagonists are useful potent and selective H3-receptor tools for in vitro studies and for investigations of ligand-receptor interactions.

Animals↗
PubMed1997

Search for novel leads for histamine H3-receptor antagonists: oxygen-containing derivatives.

This study was performed in order to develop new leads for antagonists of the histamine H3-receptor subtype. omega-(1 H-Imidazol-4-yl)alkyl derivatives with ester, ketone or alcohol functionality in the side chain were synthesized and tested concerning their H3-receptor antagonist activity on synaptosomes of rat cerebral cortex. The novel compounds, which possess no nitrogen-containing polar group in the side chain of the imidazole moiety, presented moderate to high antagonist potency in vitro. In this series 3-(1 H-imidazol-4-yl)propyl-3-cyclopentylpropanoate (4) was the most potent compound in vitro with -log Ki = 8.5. Unfortunately, no central antagonist H3-receptor activity was detectable for ester derivatives in the in vitro H3-receptor assay based upon measurement of brain N tau-methylhistamine levels after p.o. administration to mice. Some of these novel antagonists are useful tools for investigations on ligand-receptor interaction because of their distinct receptor activities. On the other hand, the ketone derivative 1-(1 H-imidazol-4-yl)-7-phenyl-4-heptanone (9) in vitro presented an ED50-value of 3.5 +/- 1.5 mg/kg p.o. thus proving to be a new lead for further drug investigations. The most potent compounds in vitro and in vivo also showed high H3-receptor selectivity when tested at other histamine receptor subtypes.

Animals↗
PubMed1996

Potential of on-line isotachophoresis-capillary zone electrophoresis with hydrodynamic counterflow in the analysis of various basic proteins and recombinant human interleukin-3.

Isotachophoresis-capillary zone electrophoresis with hydrodynamic counterflow was applied to the analysis of various basic model proteins and recombinant human interleukin-3. The use of coated capillaries and simple modifications of a commercial capillary zone electrophoresis (CZE) system allowed the detection of concentrations in the 10(-8) M region. The limit of detection was decreased by a factor of 100 compared to conventional CZE. The separation efficiency was unaffected by the preceding isotachophoretic step. Our method is applicable to the analysis of proteins with an isoelectric point higher than 7.0.

Buffers↗
PubMed1996

[125I]iodoproxyfan and related compounds: a reversible radioligand and novel classes of antagonists with high affinity and selectivity for the histamine H3 receptor.

The synthesis and biological evaluation of new histamine H3 receptor antagonists with an iodinated aryl partial structure are described as part of an extensive research program to find model compounds for the development of a new radioligand with high H3 receptor affinity and specific activity. All compounds were tested for their H3 receptor antagonist activity in a [3H]-histamine-release assay with synaptosomes from rat cerebral cortex. The new leads with potent H3 receptor antagonist activity belong to a series of derivatives of 3-(1H-imidazol-4-yl)propanol with carbamate (4-7), ester (8-16), and ether (17-22) as functional groups. Structure-activity relationships are discussed. The most active compound in the functional test (-log Ki = 8.3) and in binding studies with [3H]-(R)-alpha-methylhistamine on rat cerebral cortex (-log Ki = 9.0) in vitro was 3-(1H-imidazol-4-yl)propyl (4-iodophenyl)methyl ether (iodoproxyfan, 19) exhibiting no central H3 receptor antagonist activity in vivo. The potency of iodoproxyfan is more than 300 times lower at H1, H2, alpha1, alpha2, beta1, 5-HT2A, 5-HT3, and M3 receptors than at histamine H3 receptors. Because of the high potency and selectivity of 19, this compound has also been prepared in the [125I]-iodinated form by a nucleophilic halogen exchange reaction using the corresponding bromo derivative 22 as a precursor. The newly prepared [125I]iodoproxyfan (23) possesses advantageous pharmacological properties and fulfills all criteria of a useful radioligand.

Animals↗
PubMed1996

Novel carbamates as potent histamine H3 receptor antagonists with high in vitro and oral in vivo activity.

The known histamine H3 receptor antagonists burimamide, thioperamide, clobenpropit, and a related homohistamine thioamide derivative were taken as templates in search for new leads. Novel histamine H3 receptor antagonists structurally described as carbamate derivatives of 3-(1H-imidazol-4-yl)propanol were prepared in high yields by treatment of the alcohol with corresponding isocyanates or carbamoyl chlorides and investigated for their H3 receptor antagonist activity. Different chain lengths and various substituents possessing different electronic and steric parameters were introduced and structure-activity relationships established. In different functional tests, the new antagonists showed high H3 receptor antagonist potencies in vitro (-log Ki values of 6.4-8.4) at synaptosomes of rat cerebral cortex and low activities at histamine H1 and H2 receptor subtypes. They were also screened for their central in vivo activity in mice after peroral administration. The most promising compounds (2, 16, 19) showed ED(50) values of about 1-2 mg/kg and thus are potential drugs for the therapy of H3 receptor dependent diseases. Some of the novel carbamate derivatives are H3 receptor selective compounds with high in vitro and in vivo activity.

Administration, Oral↗
PubMed1996

Synthesis and pharmacology of combined histamine H1-/H2-receptor antagonists containing diphenhydramine and cyproheptadine derivatives.

The classical histamine H1-receptor antagonists diphenhydramine (3a) and cyproheptadine (9) and their derivatives (3b-d, 10) were connected with a 2-guanidinothiazole containing structure (28) derived from the H2-receptor antagonist tiotidine in order to obtain combined H1-/H2-receptor antagonists. The two moieties were not directly linked together, but were separated by a polymethylene spacer and a polar group (nitroethenediamine or urea). Thus 12 compounds were obtained that proved in vitro to possess high H1- and H2-receptor antagonist activity at the isolated guinea-pig ileum (H1) and the isolated guinea-pig right atrium (H2), respectively. The incorporation of the diphenhydramine as well as the cyproheptadine component provides high affinity to H1-receptors. The tricyclic cyproheptadine and its 10,11-dihydro derivative (30-32, 34), however, cause a decrease of H2-receptor antagonist potency compared to the diphenhydramines (29a-d, 33a-d). Using nitroethenediamine as the polar group is apparently more favourable to H1- and H2-receptor affinity as the urea function. All compounds elicit a dual mode of competitive and noncompetitive antagonism. Among the novel compounds the nitroethenediamines with 4-fluoro- or 4-methyl-substituted diphenhydramine as H1-receptor antagonist moiety (29c, d) display the most potent H1- and H2-receptor antagonist effects. The presented concept is a very promising way to combine H1- and H2-receptor antagonist properties in one molecule.

Animals↗
PubMed1996

New potent azomethine prodrugs of the histamine H3-receptor agonist (R)-alpha-methylhistamine containing a heteroarylphenyl partial structure.

The therapeutic value of histamine H3-receptor ligands is under current investigation. On the basis of recently described diary limine prodrugs of the histamine H3-receptor agonist (R)-alpha-methylhistamine (1) as a series of new azomethine prodrugs containing five- and six-membered heterocycles were synthesized and tested for their in vitro hydrolysis rates and in vivo activity after oral application. It was found that electron-deficient six-membered heterocycles drastically destabilized the imine double bond so that these prodrugs decomposed unsuitably fast. On the contrary, prodrugs containing five-membered heterocycles appeared to be highly effective for the CNS delivery of 1, and a remarkable correlation between chemical structure and pharmacokinetic profile was observed. Particularly (R)-4-fluoro-2-[[N-[1-(1H-imidazol-4-yl)-2-propyl]imino] (1H-pyrrol-2-yl)methyl]phenol (8c), the 2-furanyl analogue 8d, and its 3-furanyl isomer 8e proved to be equipotent to the most potent of recently described halogenated diaryl imine prodrugs of 1. However, in contrast to any other azomethine prodrug, 8c exhibited an incomparably long lasting delivery of 1 in the CNS and can thus be regarded as a 'retard' prodrug. Assuming that a therapeutic indication of histamine H3-receptor agonists will soon be established, these highly potent heteroarylphenyl azomethine prodrugs, which already serve as valuable pharmacological tools, may also become potential drugs in clinical use.

Animals↗
PubMed1996

Potencies of antagonists chemically related to iodoproxyfan at histamine H3 receptors in mouse brain cortex and guinea-pig ileum: evidence for H3 receptor heterogeneity?

We determined the affinities of 16 newly synthesized H3 receptor antagonists in an H3 receptor binding assay and the potencies of 12 of these compounds at functional H3 receptors in the mouse brain cortex and guinea-pig ileum. The compounds differ from histamine in that the C-C-N side chain is replaced by a chain of the structure C-C-C-O. The two major aims of the study were (1) to investigate whether the two functional H3 receptors are pharmacologically different and (2) to derive structure-activity relationships. The specific binding of 3H-Na-methylhistamine to rat brain cortex membranes was monophasically displaced by each of the 16 compounds at pKi values ranging from 7.30 to 9.48. In superfused mouse brain cortex slices preincubated with 3H-noradrenaline, the electrically evoked tritium overflow was slightly decreased by iodoproxyfan and its deiodo analogue; this effect was counteracted by the H3 receptor antagonist clobenpropit. The other compounds did not affect the evoked tritium overflow by themselves. The concentration-response curve of histamine for its inhibitory effect on the electrically evoked tritium overflow was shifted to the right by the 12 compounds with apparent pA2 values ranging from 7.02 to 9.00. The 12 compounds also shifted to the right the concentration-response curve of R-a-methylhistamine for its inhibitory effect on the electrically induced contraction in guinea-pig ileum strips; the apparent pA2 values ranged from 5.97 to 9.00. Iodoproxyfan decreased the electrically induced contraction by itself and this effect was counteracted by the H3 receptor antagonist thioperamide. The apparent pA2 values in the two functional H3 receptor models showed a highly significant correlation (r = 0.882; P < 0.001). Highly significant correlations were also obtained when the pKi values of the compounds in the binding assay were compared to their apparent pA2 values in the mouse brain (r = 0.799; P < 0.004) and in the guinea-pig ileum (r = 0.851; P < 0.001). In each of the three experimental models, iodoproxyfan was the most potent compound; its deiodo analogue was less potent by more than 1.1 log units. The present results show that the compounds under study possess moderate to high affinity and/or (partial) H3 receptor antagonist potency. The two functional H3 receptors in the mouse brain cortex and the guinea-pig ileum may be slightly different; further studies are necessary to clarify whether this difference is due to H3 receptor heterogeneity, species variants or differences in the efficiency of receptor coupling. The marked difference in the affinity/potency between iodoproxyfan and its deiodo analogue may suggest that a highly lipophilic residue in that part of the molecule favours a high affinity/antagonistic potency at H3 receptors.

Animals↗
PubMed1996

Cationic amphiphiles with G-protein-stimulatory activity: studies on the role of the basic domain in the activation process.

2-Substituted histamines, which are cationic-amphiphilic, activate pertussis toxin-sensitive G-proteins by a receptor-independent mechanism. Lipophilicity is an important determinant for this G-protein activation, but the influence of basicity remained unclear. We prepared four imidazole-containing compounds and nine alkylamines with different basicity and studied their effcts on high-affinity GTP hydrolysis in HL-60 membranes. The substances contained a lipophilic domain (L) and polar (P) and/or cationic (C) domains. Compared to 2-substituted histamines (L-P-C), the corresponding L-C-P type compounds were less potent and effective which, however, were still more active than L-P-P type substances. Among alkylamines, 2-octadecylaminoethyl-N,N-diethylamine (11) was the most potent GTPase activator (pEC50 = 5.7; 100% stimulation above basal). Conversely, 3-(5-hydroxyundecylamino)propylamine (15) was the most efficient compound (pEC50 = 4.3; 160% stimulation above basal). Compared to compounds 11 and 15, which belong to the L-C-C type, the corresponding L-P-C type compounds were less active. Thus, among 2-substituted histamines and alkylamines, a terminal cationic domain is critical for potent and/or effective receptor-independent G-protein activation. An L-C-X structure (X = P or C) is more favorable for G-protein activation than a L-P-X structure. Potency and efficiency of receptor-independent G-protein activators are independently determined drug parameters.

Animals↗
PubMed1996

Structure-activity relationships of novel azomethine prodrugs of the histamine H3-receptor agonist (R)-alpha-methylhistamine: from alkylaryl to substituted diaryl derivatives.

This study was performed on the basis of recently developed prodrugs of the histamine H3-receptor agonist (R)-alpha-methylhistamine (1) to determine structure-activity relationships of azomethine prodrugs of 1, in which the primary amine functionality is bioreversibly linked to aromatic ketones. Therefore, the pro-moiety was systematically altered from alkylaryl over benzylaryl to diaryl substitution. Those compounds that emerged to be stable enough during preparation were tested for their in vitro hydrolysis rates. Apparently, bulky alkyl residues were capable of preventing previously observed intramolecular cyclization, but the obtained azomethines 12a-c were far too unstable to serve as prodrugs. However, the benzylaryl imines 12d, e were stable compounds, but 12d decomposed too rapidly under in vitro conditions. Distinctly greater stability was provided by diaryl pro-moieties, even if strongly electron-withdrawing functionalities were introduced. Selected compounds were also tested in vivo following p.o. application to mice. Particularly the trifluoromethyl substituted imine 12i proved to be highly effective as stability and rate of conversion were well-balanced, so that brain penetration of 1 was strikingly facilitated. Thus 12i, a highly potent azomethine prodrug, may serve as an important pharmacological tool and, possibly, a therapeutic agent.

Animals↗