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Biomedical subjects

W Schunack

Publications and source records attributed to W Schunack.

At least 55 records · Page 3Linked to original sources
PubMed2000

Histaprodifens: synthesis, pharmacological in vitro evaluation, and molecular modeling of a new class of highly active and selective histamine H(1)-receptor agonists.

A new class of histamine analogues characterized by a 3, 3-diphenylpropyl substituent at the 2-position of the imidazole nucleus has been prepared outgoing from 4,4-diphenylbutyronitrile (4b) via cyclization of the corresponding methyl imidate 5b with 2-oxo-4-phthalimido-1-butyl acetate or 2-oxo-1,4-butandiol in liquid ammonia, followed by standard reactions. The title compounds displayed partial agonism on contractile H(1) receptors of the guinea-pig ileum and endothelium-denuded aorta, respectively, except 10 (histaprodifen; 2-[2-(3, 3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) which was a full agonist in the ileum assay. While 10 was equipotent with histamine (1), methylhistaprodifen (13) and dimethylhistaprodifen (14) exceeded the functional potency of 1 by a factor of 3-5 (13) and 2-3 (14). Compounds 10 and 13-17 relaxed precontracted rat aortic rings (intact endothelium) with relative potencies of 3.3- up to 28-fold (compared with 1), displaying partial agonism as well. Agonist effects were sensitive to blockade by the selective H(1)-receptor antagonist mepyramine (pA(2) approximately 9 (guinea-pig) and pA(2) approximately 8 (rat aorta)). The affinity of 10 and 13-17 for guinea-pig H(1) receptors increased 20- to 100-fold compared with 1. Two lower homologues of 10 were weak partial H(1)-receptor agonists while two higher homologues of 10 were silent antagonists endowed with micromolar affinity for rat and guinea-pig H(1) receptors. In functional selectivity experiments, 10, 13, and 14 did not stimulate H(2), H(3), and several other neurotransmitter receptors. They displayed only low to moderate affinity for these sites (pA(2) < 6). For a better understanding of structure-activity relationships, the interaction of 1 and 10, 13 and 14 within the transmembrane (TM) domains of the human histamine H(1) receptor were studied using molecular dynamics simulations. Remarkable differences were found between the binding modes of 10, 13, and 14 and that of 1. The imidazole ring of 10, 13, and 14 was placed 'upside down' compared with 1, making the interaction of the N(pi)-atom with Tyr431 possible. This new orientation was mainly caused by the space filling substitution at the 2-position of the imidazole ring and influenced the location of the protonated N(alpha)-atom which was positioned more between TM III and TM VI. This orientation can explain both the increased relative potency and the maximum effect of 10, 13, and 14 compared with 1. Compound 13 (methylhistaprodifen; N(alpha)-methyl-2-[2-(3, 3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine) is the most potent histamine H(1)-receptor agonist reported so far in the literature and may become a valuable tool for the study of physiological and pathophysiological H(1)-receptor-mediated effects.

Animals↗
PubMed2000

Ring-substituted histaprodifen analogues as partial agonists for histamine H(1) receptors: synthesis and structure-activity relationships.

Thirteen racemic benzene ring-substituted analogues of histaprodifen (8a; 2-[2-(3,3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine), a novel lead for potent and selective histamine H(1)-receptor agonists, have been prepared from substituted 4,4-diphenylbutyronitriles 5 via cyclization of the corresponding methyl butyrimidates 6 with 2-oxo-4-phthalimido-1-butyl acetate in liquid ammonia, followed by deprotection. Nitriles 5 were accessible by alkylation of either substituted diphenylmethanes with 3-bromopropionitrile or diethyl malonate with substituted 1-chloro-diphenylmethanes and subsequent standard reactions. The title compounds 8 displayed partial agonism on contractile H(1) receptors of the guinea-pig ileum (E(max) = 2-98% relative to histamine) and, compared with the endogenous agonist, were endowed with agonist potencies of 4-92%. The meta fluorinated (8c) and meta chlorinated (8f) analogues showed the highest relative potency in this series (95% confidence limits 85-99% and 78-102%), but did not exceed the value of the lead 8a (99-124%). Compound 8c (2-[2-[3-(3-fluorophenyl)-3-phenylpropyl]-1H-imidazol-4-yl]ethanamine ) was a partial agonist at contractile H(1) receptors of the guinea-pig aorta (relative potency 154% vs. 100% for histamine) and at relaxation-mediating endothelial H(1) receptors of the rat aorta (relative potency 556% vs. 100% for histamine) and matched with the functional behaviour of 8a. Agonism observed for each compound was sensitive to blockade by the selective H(1)-receptor antagonist mepyramine (pA(2) approximately 9 (guinea-pig) and pA(2) approximately 8 (rat aorta)). All histaprodifen analogues 8 stimulated neither histaminergic H(2)/H(3) nor cholinergic M(3) receptors. They displayed only low to moderate affinity for these sites (H(2): pD'(2) < 5; H(3)/M(3): pA(2) < 6). With regard to the substitution pattern on the benzene ring, there was no correlation between the histaprodifen series and the corresponding derivatives of another selective H(1)-receptor agonist, viz. 2-phenylhistamine.

Animals↗
PubMed2000

(Partial) agonist/antagonist properties of novel diarylalkyl carbamates on histamine H3 receptors.

In the search for new ligands of the histamine H3 receptor, novel diarylalkyl carbamates (1-19) were synthesized as derivatives of 3-(1H-imidazol-4-yl)propanol and -ethanol. Carbamates were built up via isocyanates either from corresponding amines by reaction with diphosgene or from related carboxylic acid/diphenylphosphoryl azide and the alcoholic component. Sterically hindered amines were prepared in a two-step reaction sequence from corresponding ketones. Some of the title compounds showed (partial) agonist activity at the histamine H3 receptor in vitro and in vivo. Diphenylmethyl carbamate 2 was identified as a new lead structure (ED50 = 5.3 +/- 2.6 mg/kg po, alpha = 1.0). Aromatic substitution in ortho- or para-positions of 2 led to a loss of agonist activity. meta-Substitution was tolerated to some extent. These effects seemed to be caused by steric rather than electronic properties of the substituents. An investigation of exchange of one or both phenyl rings of 2 by heterocyclic rings led to the highly active and selective thienyl derivative 18 (ED50 3.4 +/- 1.4 mg/kg p.o., alpha = 1.0). These new (partial) agonists of the histamine H3 receptor might serve as pharmacological tools for investigating molecular aspects of the H3 receptor or as possible centrally acting therapeutic agents with oral bioavailability.

Animals↗
PubMed2000

Histamine H(3)-receptor antagonists inhibit gastroprotection by (R)-alpha-methylhistamine in the rat.

(R)-alpha-methylhistamine, a selective agonist of histamine H(3) receptors, is capable of protecting the gastric mucosa against differently acting damaging agents. The objective of the present study was to determine whether H(3) receptors mediate its protective action in the rat. Gastric mucosal lesions were induced intragastrically (i.g.) by 0.6 N HCl, 1 ml rat(-1). (R)-alpha-methylhistamine, 100 mg kg(-1) i.g., substantially reduced the severity of macroscopically and histologically assessed damage caused by concentrated acid. Prior treatment with highly selective H(3)-receptor antagonists, ciproxifan (0.3, 1 and 3 mg kg(-1) i.g.) and clobenpropit (3, 10 and 30 mg kg(-1) i.g.), dose-dependently inhibited the protection exerted by (R)-alpha-methylhistamine up to a complete reversal. When given alone at high doses, both antagonists tended to worsen the HCl-induced histologic damage. During basal conditions, (R)-alpha-methylhistamine, 100 mg kg(-1) i. g., caused a significant increase in titratable acidity of the gastric juice. Prior treatment with ciproxifan (3 mg kg(-1) i.g.) and clobenpropit (30 mg kg(-1) i.g.) did not alter the secretory response to (R)-alpha-methylhistamine. Clobenpropit alone, but not ciproxifan, increased the volume of gastric juice, and both compounds alone had no effect on titratable acid. Present findings support evidence that H(3) receptors are actively involved in the maintenance of gastric mucosal integrity, with no apparent role in the regulation of basal gastric acid secretion.

Animals↗
PubMed2000

Distinct pharmacology of rat and human histamine H(3) receptors: role of two amino acids in the third transmembrane domain.

Starting from the sequence of the human histamine H(3) receptor (hH(3)R) cDNA, we have cloned the corresponding rat cDNA. Whereas the two deduced proteins show 93.5% overall homology and differ only by five amino acid residues at the level of the transmembrane domains (TMs), some ligands displayed distinct affinities. Thioperamide and ciproxifan were about 10 fold more potent at the rat than at the human receptor, whereas FUB 349 displayed a reverse preference. Histamine, (R)alpha-methylhistamine, proxyfan or clobenpropit were nearly equipotent at H(3) receptors of both species. The inverse discrimination patterns of ciproxifan and FUB 349 were partially changed by mutation of one amino acid (V122A), and fully abolished by mutation of two amino acids (A119T and V122A), in TM3 of the rH(3)R located in the vicinity of Asp(114) purported to salt-link the ammonium group of histamine. Therefore, these two residues appear to be responsible for the distinct pharmacology of the H(3)R in the two species.

Amino Acid Sequence↗
PubMed2000

Substituted N-phenylcarbamates as histamine H3 receptor antagonists with improved in vivo potency.

Novel substituted N-phenylcarbamates as derivatives of 3-(1 H-imidazol-4-yl)propanol were prepared and tested for their antagonist potency in vitro and in vivo at histamine H3 receptors. Structural modifications with different alkyl and acetyl moieties were performed in an attempt to optimize pharmacodynamic and pharmacokinetic effects. Most compounds are active in a functional test for histamine H3 receptors on rat cerebral cortex synaptosomes as well as in a peripheral model on guinea pig ileum. But only carbamates without too bulky lipophilic residues showed pronounced to high antagonist potency on the enhancement of endogenous histamine in brain after p.o. administration to mice (ED50 values of 5.5 to 0.86 mg.kg-1). The tested compounds presented weak activities at histamine H1, H2, and muscarinic M3 receptors thus demonstrating their H3-receptor selectivity.

Animals↗
PubMed2000

Anti-inflammatory and antinociceptive properties of BP 2-94, a histamine H(3)-receptor agonist prodrug.

BP 2-94 is an azomethine prodrug of (R)-alpha-methylhistamine [(R)-alpha-MeHA], a potent and selective histamine H(3)-receptor agonist. When administered orally to mice BP 2-94 was distributed to various peripheral tissues where it released the active drug. BP 2-94 displayed anti-inflammatory and antinociceptive properties in mice. It dose-dependently inhibited carrageenan-induced paw edema with an ED(50) value of 0.17 +/- 0.05 micromol/kg (p.o.) and a maximal effect of 47%. It also reduced Freund's complete adjuvant-induced paw edema in preventive as well as in curative fashion. Repeated oral administrations of BP 2-94 reduced the pre-established Freund's complete adjuvant-induced edema with an ED(50) value of 5 +/- 2 micromol/kg (p.o.) and a maximal effect of 47%. The antiedema effects of BP 2-94 and indomethacin were additive. BP 2-94 was also efficient in reducing cyclophosphamide-induced cystitis in mice: it decreased leukocyte infiltration by 62% and plasma protein extravasation by 73% in urinary bladder. In addition, BP 2-94 displayed antinociceptive activity in the capsaicin-induced licking test via H(3)-receptor stimulation. Its antinociceptive effect was dose dependent, occurring with an ED(50) value of 0.4 +/- 0.1 micromol/kg (p.o.) and a maximal reduction of licking duration by 69%. No tolerance to the antinociceptive effect was observed after repeated administration of BP 2-94 for 3 days. These observations with BP 2-94 suggest that H(3)-receptor agonists might represent a novel class of anti-inflammatory and antinociceptive agents.

Analgesics↗
PubMed2000

Importance of the lipophilic group in carbamates having histamine H3-receptor antagonist activity.

In order to evaluate changes in the lipophilic part of designed carbamates concerning their potential histamine H3-receptor antagonist properties a new series of O-[3-(1H-imidazol-4-yl)propanol]carbamates was derived containing N-mono- or di-alkenyl, alkynyl, cycloalkyl, or double-branched alkyl substituents. The compounds were tested in vitro for their H3-receptor antagonist activity on synaptosomes of rat cerebral cortex and shared moderate to high antagonist activity in vitro. In this series 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate (4) was the most potent compound in vitro (Ki = 6.3 nM). H3-receptor antagonist activity in the central nervous system (CNS) was detected for most compounds in the in vivo H3-receptor assay based upon measurement of brain N tau-methylhistamine levels after p.o. administration to mice. The most effective carbamate in vivo, 3-(1H-imidazol-4-yl)propyl N-(allyl)carbamate (3), showed higher CNS potency (ED50 = 0.48 mg/kg p.o.) than the reference antagonist thioperamide. For some novel carbamates their histamine H1- and H2-receptor activities were determined on isolated organs of guinea-pig thereby demonstrating their high H3-receptor selectivity.

Animals↗
PubMed1999

Novel partial agonists for the histamine H(3) receptor with high in vitro and in vivo activity.

Novel branched N-alkylcarbamates and aliphatic ethers derived from 3-(1H-imidazol-4-yl)propanol were prepared. The compounds were investigated on two functional histamine H(3)-receptor assays. Some compounds displayed partial agonist activity on synaptosomes of rat brain cortex but behaved as pure competitive antagonists on the guinea pig ileum. Under in vivo conditions after po application to mice, some of the compounds showed partial or full agonist activity. Highest in vivo potency was found for the 3,3-dimethylbutyl ether 10 (ED(50) = 0.29 mg/kg, full intrinsic activity). These novel agonists are structurally diverse from classical aminergic histamine H(3)-receptor agonists (e.g., (R)-alpha-methylhistamine, imetit) as they lack a basic moiety in the side chain, which is supposed to be important for the activation of the receptor protein. The selectivity for the histamine H(3) receptor was proven by determination of H(1)- and H(2)-receptor activity on functional assays of the guinea pig.

Animals↗
PubMed1999

Utility of isotachophoresis-capillary zone electrophoresis, mass spectrometry and high-performance size-exclusion chromatography for monitoring of interleukin-6 dimer formation.

The utility of isotachophoresis-capillary zone electrophoresis (ITP-CZE) and high-performance size-exclusion chromatography (HPSEC) was investigated for determination of dimeric and monomeric recombinant human interleukin-6 (rhIL-6). Using ITP-CZE heterogeneity of dimeric rhIL-6 could be revealed resolving two peaks in the electropherograms, while with HPSEC dimeric rhIL-6 eluted as one homogeneous fraction. Both protein forms were monitored during incubation of monomeric rhIL-6 at different pH and temperature. The selectivity of counterflow ITP-CZE in conjunction with the low concentration determination limits enabled reanalysis of HPSEC fractions for identification of the dimer in the electropherograms. Both ITP-CZE and HPSEC were shown to be suitable to monitor the dimerization of rhIL-6, similar monomer-to-dimer peak area ratios were obtained throughout the incubation. Dimer formation kinetics increased with decreasing pH and with increasing temperature, it was entirely suppressed at neutral pH and room temperature. In contrast to HPSEC, ITP-CZE enabled separation of further still unidentified artifacts apparently formed during incubation of rhIL-6. CZE analysis in conjunction with electrospray ionization mass spectrometry revealed the non-covalent binding character of the dimeric rhIL-6 complex and facilitated interpretation of the electropherograms.

Chromatography, Gel↗
PubMed1999

Development of chiral N-alkylcarbamates as new leads for potent and selective H3-receptor antagonists: synthesis, capillary electrophoresis, and in vitro and oral in vivo activity.

Novel carbamates as derivatives of 3-(1H-imidazol-4-yl)propanol with an N-alkyl chain were prepared as histamine H3-receptor antagonists. Branching of the N-alkyl side chain with methyl groups led to chiral compounds which were synthesized stereospecifically by a Mitsunobu protocol adapted Gabriel synthesis. The optical purity of some of the chiral compounds was determined (ee > 95%) by capillary electrophoresis (CE). The investigated compounds showed pronounced to high antagonist activity (Ki values of 4.1-316 nM) in a functional test for histamine H3 receptors on rat cerebral cortex synaptosomes. Similar H3-receptor antagonist activities were observed in a peripheral model on guinea pig ileum. No stereoselective discrimination for the H3 receptor for the chiral antagonists was found with the in vitro assays. All compounds were also screened for central H3-receptor antagonist activity in vivo in mice after po administration. Most compounds were potent agents of the H3-receptor-mediated enhancement of brain Ntau-methylhistamine levels. The enantiomers of the N-2-heptylcarbamate showed a stereoselective differentiation in their pharmacological effect in vivo (ED50 of 0.39 mg/kg for the (S)-derivative vs 1.5 mg/kg for the (R)-derivative) most probably caused by differences in pharmacokinetic parameters. H1- and H2-receptor activities were determined for some of the novel carbamates, demonstrating that they have a highly selective action at the histamine H3 receptor.

Administration, Oral↗
PubMed1999

Monitoring of chemotherapy-induced proteinuria using capillary zone electrophoresis.

Capillary zone electrophoresis (CZE) was investigated for its suitability to monitor proteinuria occurring during nephrotoxic drug therapy. Urine samples of tumor patients receiving chemotherapy consisting of carboplatin, etoposide, and ifosfamide were concentrated and desalted in microconcentrators and analyzed in two different alkaline CZE buffer systems. Reduction of electroosmotic flow (EOF) by the addition of putrescine increased the number of resolved protein peaks. Both CZE methods were linear between 2.5 and 50 microg/ml, exhibited satisfactory precision (relative standard deviation <10%) and were suitable for monitor the time course of proteinuria after chemotherapy administration. In contrast to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), CZE detected interindividual differences in protein patterns. Whereas these differences hampered a direct quantification of proteins in urine, they may contain information on the type or extent of kidney damage.

Adult↗
PubMed1999

Histaprodifen, methylhistaprodifen, and dimethylhistaprodifen are potent H1-receptor agonists in the pithed and in the anaesthetized rat.

Selective H2- and H3-receptor agonists, exhibiting an at least tenfold higher potency than histamine itself at the respective receptors, have been known for several years. Selective H1-receptor agonists with a potency exceeding that of histamine have become available only recently; the most potent are methylhistaprodifen and dimethylhistaprodifen [Nalpha-methyl- and Nalpha,Nalpha-dimethyl-2(3,3-diphenylpropyl)histamine, respectively] with 3.4- and 2.4-fold higher potencies than histamine in vitro (in the guinea-pig ileum). The aim of the present study was to examine whether these compounds and the parent compound histaprodifen are potent H1-receptor agonists in the pithed and in the anaesthetized rat. In pithed, vagotomized rats diastolic blood pressure was decreased by 2-(2-thiazolyl)ethanamine i.v. (which was used as a reference H1-receptor agonist) and by histaprodifen, methylhistaprodifen, and dimethylhistaprodifen; the maximum decrease was about 45 mmHg for each compound, and the potencies, expressed as pED50, the negative logarithm of the dose (in mole per kilogram body weight) eliciting a half-maximal response, were 7.23, 7.55, 8.43 and 8.12, respectively. The dose/response curves of the four compounds were shifted to the right to about the same extent by the H1-receptor antagonist dimetindene (1 micromol/kg i.v.). The vasodepressor response was not affected by combined i.v. administration of the H2- and H3-receptor antagonists ranitidine and thioperamide, by combined i.v. administration of the alpha1- and alpha2-adrenoceptor antagonists prazosin and rauwolscine, and by the beta-adrenoceptor antagonist propranolol i.v. but was attenuated by the inhibitor of NO synthase, N(omega)-nitro-L-arginine methyl ester i.v. In anaesthetized rats 2-(2-thiazolyl)ethanamine, histaprodifen, methylhistaprodifen and dimethylhistaprodifen i.v. also decreased diastolic blood pressure in a manner sensitive to dimetindene i.v. Our data show that histaprodifen and, in particular, methyl and dimethylhistaprodifen are highly potent H1-receptor agonists in vivo.

Anesthesia↗
PubMed1999

Radiosynthesis and biodistribution of 123I-labeled antagonists of the histamine H3 receptor as potential SPECT ligands.

We have synthesized three 123I-labeled histamine H3 receptor ligands, i.e., [123I]GR 190028, [123I]FUB 271, and [123I]iodoproxyfan, in moderate to good radiochemical yields via a Cu+-assisted I-for-123I exchange method. Biodistribution in the rat of these compounds revealed high hepatic and pulmonary uptake. Brain uptake was moderate, but for [123I]iodoproxyfan, brain uptake was high enough for a pilot single photon emission computed tomography (SPECT) study in the rabbit. However, for this compound, the cerebral uptake could not be blocked by a pretreatment with [R]-alpha-methylhistamine, a selective, high-affinity histamine H3 receptor agonist, both in the SPECT study in the rabbit and in the biodistribution study in the rat. Apparently, [123I]iodoproxyfan is binding to a non-H3 receptor binding site. None of the three investigated compounds is suitable for use as a SPECT ligand for the H3 receptor in the brain.

Animals↗
PubMed1999

Pharmacokinetic and pharmacodynamic comparison of two doses of calcium folinate combined with continuous fluorouracil infusion in patients with advanced colorectal cancer.

The optimum dose of calcium folinate (leucovorin) as modulator of fluorouracil has not been defined yet. We conducted a randomized trial to compare the pharmacokinetics/pharmacodynamics of two doses of calcium folinate. 16 patients with advanced colorectal cancer were treated with 650 mg/m2/d fluorouracil as 5 day continuous infusion and randomized to receive either 20 mg/m2 or 100 mg/m2 calcium folinate as short infusion twice daily. The two diastereoisomers of calcium folinate were analyzed separately by chiral HPLC to account for differences in their pharmacokinetics. The pharmacokinetics of fluorouracil was not affected by folinate dosing. Total clearance of the active (6S)-diastereoisomer was found to be lower after the higher dose of folinate which can be explained by nonlinear metabolism. The incidence of treatment-induced mucositis significantly increased with (6S)-folinate exposure, whereas fluorouracil exposure was not related to this type of toxicity. In conclusion, exposure to folinate is more important for toxicity in this regimen than fluorouracil pharmacokinetics. Therefore, monitoring of fluorouracil plasma levels is not useful in this combination. Our results show that folinate dose should be carefully selected. Lower doses of folinate might be preferred because of less toxicity compared to higher doses.

Aged↗
PubMed1999

Determination of platinum complexes in clinical samples by a rapid flameless atomic absorption spectrometry assay.

The frequent use of platinum (Pt) complexes in cancer chemotherapy and the application of new therapeutic options and dosing strategies have increased the need for rapid analytic procedures to determine Pt concentrations in the biologic fluids of patients. Therefore a flameless atomic absorption spectrometry method for the quantification of Pt in plasma and ultrafiltrate was developed and validated. A simple sample preparation of only one dilution step was established. Only 400 microL of whole blood was required for duplicate analysis of Pt in both matrices. The matrix-specific temperature programs took less than 75 seconds. The lower limit of quantification was 40 ng Pt/mL and 20 ng Pt/mL for plasma and ultrafiltrate, respectively. Suitable linearity could be reached using separate calibration curves for the high and low Pt concentration ranges. Recovery of Pt was complete, and there were no major stability problems. The accuracy and precision of the new method met the international criteria for the validation of bioanalytic methods. In addition, the use of different anticoagulants for clinical sampling, ultrafiltration systems, and ultrafiltration conditions were investigated. The assay has already been extensively applied to pharmacokinetic studies. In conclusion, the new Pt assay proved to be rapid, simple, sensitive, and suitable for clinical use.

Anticoagulants↗