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Biomedical subjects

A Buschauer

Publications and source records attributed to A Buschauer.

At least 55 records · Page 3Linked to original sources
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

Structure-activity relationships of histamine H2-agonists, a new class of positive inotropic drugs.

The cimetidine-like moiety in impromidine was replaced by either alternative partial structures known from H2-antagonists or by H2-nonspecific lipophilic groups. The most potent H2-agonists were found in a series of compounds structurally derived from the H1-antagonist pheniramine. Arpromidine (N1-[3-(4-fluorophenyl)-3-(2-pyridinyl)propyl]-N2-[3-(1H-imidazol-4- yl)propyl]guanidine) may be considered a new lead for the development of "cardiohistaminergics". This guanidine combines both about 100 times the potency of histamine in the isolated guinea-pig atrium (pD2 = 8.0) and H1-antagonistic activity (pA2 = 7.65) in the range of pheniramine. Analogues difluorinated in 3,4-(BU-E-75) or 3,5-position (BU-E-76) or chlorinated in 3,4-position (BU-E-64) are up to 160 times more potent H2-agonists than histamine. In contrast to other types of guanidines, in the arpromidine series the order of potency found in guinea-pig atria was in good agreement with the results from isolated perfused guinea-pig hearts. In particular, the two-fold halogenated arpromidine analogues proved to be more potent positive inotropic agents than impromidine with lower stimulating effects on heart rate and reduced arrhythmogenic properties.

Animals↗
PubMed1991

Therapeutic value of H2-receptor stimulation in congestive heart failure. Hemodynamic effects of BU-E-76, BU-E-75 and arpromidine (BU-E-50) in comparison to impromidine.

Previous studies from our department revealed that congestive heart failure (CHF) is paralleled by a decrease in number of sarcolemmal beta-receptors due to excessive levels of circulating endogenous catecholamines. In contrast, the myocardial H2-receptor system proved to be not affected (Am. Heart J. 101; 569, 1981). The first clinically tested specific H2-receptor agonist impromidine (IMP) turned out to be a potent stimulator in patients with CHF which were insensitive to catecholamine stimulation (Pharmacol. Ther. 24; 165, 1984). Though the overall results of such an H2-receptor stimulation were salutary with favourable hemodynamic effects, the narrow therapeutic range, high costs of synthesis and the arrhythmogenic potential of IMP limited its broad clinical application in large scale trials. - Recently developed phenylpyridylalkylguanidines (J. Med. Chem. 32, 1963, 1989) were investigated under in vitro and in vivo conditions in the guinea-pig under physiologic and pathophysiologic conditions using IMP as reference. - Compounds tested were arpromidine (INN) (BU-E-50) and the difluorinated analogues BU-E-75 and BU-E-76, all guanidine-type H2-agonists with additional H1-antagonistic properties due to a pheniramine like moiety. In the isolated perfused heart all three new compounds were more potent in increasing cardiac contractile force and coronary flow but less effective on heart rate and less arrhythmogenic. The same could be established under in vivo conditions where BU-E-76 was more potent than BU-E-75, arpromidine and IMP, respectively, in augmenting LVdp/dt, LVP, cardiac output and systemic blood pressure, but all compounds revealed to have less chronotropic and arrhythmogenic potentials. In the vasopressin-induced acute heart failure model BU-E-76 and BU-E-75 normalized all contractile parameters in contrast to arpromidine and IMP. Within minutes it is concluded that the new H2-receptor agonists may represent a promising therapeutic improvement for treatment of CHF patients with a cardiovascular profile superior to IMP and conventional catecholamines.

Animals↗
PubMed1991

Synthesis and histamine H2-agonistic activity of ring-substituted phenyl analogues of impromidine.

Analogues of the H2-agonist impromidine, characterized by a substituted phenyl ring instead of the 5-methyl-4-imidazolyl group, were prepared and tested for their H2-agonistic and H1-antagonistic activity at the guinea-pig atrium and ileum, respectively. The compounds were synthetized via successive aminolysis of diphenyl benzoylcarbonimidate and final acid hydrolysis of the benzoylguanidines. The substituents (mono- or disubstitution with F, Cl, Br, CF3, Me, Et, NO2, NMe2, NEt2, PhCH2) were mainly selected according to the structure-activity relationships known from potent cardiohistaminergics such as arpromidine. While in the arpromidine series substitution of the phenyl ring, in particular halogenation, proved to be very useful for increasing potency, in the series of title compounds, except for the m-fluoro analogue 5g, these variations resulted in a decrease in H2-agonistic activity in the isolated guinea-pig right atrium up to 1.5 orders of magnitude related to the parent compound 5a, which is 10 times more potent than histamine.

Animals↗
PubMed1990

Characterization of histamine H2-receptors in human neutrophils with a series of guanidine analogues of impromidine. Are cell type-specific H2-receptors involved in the regulation of NADPH oxidase?

Human neutrophils possess an NADPH oxidase which catalyzes superoxide (O2-) formation and is activated by chemotactic peptides. Histamine inhibits O2- formation via H2-receptors (Burde et al. 1989). We characterized the neutrophil H2-receptor with a series of new guanidine-type H2-agonists structurally derived from impromidine. Histamine inhibited O2- formation with an IC50 value of 6.7 +/- 1.2 microM. Five aryloxy- and arylthioalkylguanidines were less potent and effective than histamine. Several arpromidine-like phenyl(pyridylalkyl)guanidines were either full or partial H2-agonists. Some guanidines possess a three-membered carbon chain connecting the aromatic rings and the guanidine group; they were similarly potent and effective as histamine. Shortening or elongation of the carbon chain substantially decreased the potency and intrinsic activity of the guanidines. Halogenation of the phenyl ring did not substantially affect the potency and intrinsic activity of the compounds in comparison to the non-substituted parent compound. The H2-antagonist, famotidine, competitively antagonized inhibition of O2- formation caused by the guanidine, arpromidine, with a pA2 value of 6.84. The H2-antagonist, cimetidine, differentially counteracted inhibition caused by partial and full H2-agonists. Partial H2-agonists antagonized the effects of histamine. The inhibitor of phosphodiesterases, 3-isobutyl-1-methylxanthine, additively enhanced the inhibitory effects of histamine and guanidines. The properties of the neutrophil H2-receptor were compared with literature data concerning properties of the H2-receptor of the guinea pig atrium. In the latter system, guanidines are full H2-agonists with potencies of up to 125-fold of that of histamine. Our data indicate that guanidines inhibit O2- formation in human neutrophils via H2-receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1990

Reversible and irreversible labeling and autoradiographic localization of the cerebral histamine H2 receptor using [125I]iodinated probes.

Iodoaminopotentidine (I-APT)--i.e., N-[2-(4-amino-3-iodobenzamido)ethyl]-N'-cyano-N''-(3-[3- (1-piperidinylmethyl)phenoxy]propyl)guanidine--represents one of the most potent H2-receptor antagonists known so far. In membranes of guinea pig brain 125I-APT bound reversibly, selectively, and with high affinity (Kd = 0.3 nM) to a homogeneous population of sites unambiguously identified as H2 receptors by inhibition studies conducted with a large panel of antagonists. 125I-APT binding was also inhibited by histamine, and the effect was modulated by a guanyl nucleotide, which is consistent with the association of the H2 receptor with a guanine nucleotide binding regulatory protein. The low nonspecific binding of 125I-APT generated high contrast autoradiographic pictures in brain sections and established the precise distribution of H2 receptors. Their highly heterogeneous distribution and laminated pattern in some areas--e.g., cerebral and hippocampal cortices--suggest their major association with neuronal elements. These localizations were more consistent than those of H1 receptors with the distribution of histaminergic projections, indicating that H2 receptors mediate a larger number of postsynaptic actions of histamine--e.g., in striatum. Colocalizations of H1 and H2 receptors in some areas account for their known synergistic interactions in cAMP formation induced by histamine. The distribution of 125I-APT binding sites did not strictly parallel that of the H2-receptor-linked adenylate cyclase activity, which may reflect heterogeneity among H2 receptors. After UV irradiation and SDS/PAGE analysis, [125I]iodoazidopotentidine (125I-AZPT), a photoaffinity probe derived from 125I-APT, was covalently incorporated in several peptides, among which the labeling of two peptides of 59 and 32 kDa was prevented by H2 antagonists, suggesting that they correspond to H2-receptor binding peptides or proteolysis products of the latter. These probes should be useful for sensitive radioassays, localization, purification, and molecular studies of the H2 receptor, which were previously impracticable.

Affinity Labels↗
PubMed1989

[Quinazolinones. 16. Synthesis and in vitro pharmacology of 2-aryl-1- ([3-(imidazol-4-yl)propyl]-guanidinylalkyl)-2,3-dihydro-4(1H)- quinazolinones].

A series of 2-aryl-1- ([3-(imidazol-4-yl)propyl]guanidinylalkyl)-2,3-dihydro-4(1H)- quinazolinones were prepared starting with appropriate aminoalkyl-quinazolinones. The substances proved to be moderate H1-antagonists at the isolated guinea-pig ileum as well as H2-agonists, maximally achieving 1.6 times the activity of histamine at the isolated guinea-pig right atrium. Compounds with a three-membered carbon chain connecting the bicyclus and the guanidine system are up to 100 times more active at the atrium (chronotropic effect) than the corresponding lower homologues.

Animals↗
PubMed1989

Histamine inhibits activation of human neutrophils and HL-60 leukemic cells via H2-receptors.

The effects of prostaglandin E1 (PGE1) and histamine on activation of superoxide (O2-) formation, exocytosis of beta-glucuronidase and aggregation in human neutrophils and HL-60 leukemic cells were studied. PGE1, histamine and impromidine, a potent H2-agonist, inhibited O2- formation in neutrophils induced by the chemotactic peptide, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMet-Leu-Phe) with IC50 values of 0.5 microM, 8 microM and 2 microM, respectively. The full H1-agonist and weak partial H2-agonist, betahistine, was much less potent and effective than histamine. Dibutyryl cyclic AMP and forskolin mimicked the effects of histamine and PGE1 on O2- formation. The H2-antagonist, famotidine, competitively reversed histamine-induced inhibition of O2- formation with a pA2 value of 7.5. Histamine inhibited O2- formation when added prior to or after fMet-Leu-Phe. fMet-Leu-Phe-induced aggregation and release of beta-glucuronidase in neutrophils were less sensitive to inhibition by PGE1, histamine, dibutyryl cyclic AMP and forskolin than O2- formation. The inhibitor of cyclic AMP-specific phosphodiesterase, rac-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 20-1724), additively enhanced the inhibitory effects of histamine and PGE1 on the above cell functions. In HL-60 cells differentiated by dimethyl sulfoxide or dibutyryl cyclic AMP, histamine, impromidine and PGE1 but not betahistine inhibited fMet-Leu-Phe-induced O2- formation as well. Our data suggest that histamine inhibits activation of neutrophils and HL-60 cells via H2-receptors through activation of adenylyl cyclase and increased formation of cyclic AMP.(ABSTRACT TRUNCATED AT 250 WORDS)

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed1989

Synthesis and in vitro pharmacology of arpromidine and related phenyl(pyridylalkyl)guanidines, a potential new class of positive inotropic drugs.

Replacement of the cimetidine moiety in impromidine (1,N1-[3-(1H-imidazol-4-yl)propyl]-N2-[2-[[(5-methyl-1H-imidazol-4- yl)methyl]thio]ethyl]guanidine) by more lipophilic H2-nonspecific pheniramine-like structures resulted in potent H2 agonists with up to 160 times the activity of histamine in the isolated, spontaneously beating guinea pig right atrium. Additionally, the compounds proved to be moderate H1 antagonists. Highest H2-agonistic potency was found in compounds characterized by a three-membered carbon chain connecting the aromatic rings and the guanidine group. The activity in the atrium was increased 2-4-fold by halogen substituents in the meta or para position of the phenyl ring. Highest H1-antagonistic potency resides in the group of para-halogenated compounds, p-F representing the optimal substituent in both receptor models. The corresponding guanidine 52 (arpromidine, N1-[3-(4-fluorophenyl)-3-pyridin-2-ylpropyl]-N2-[3-(1H-imidazol-4- yl)propyl]guanidine) combines about 100 times the activity of histamine at the H2 receptor with H1-antagonistic potency in the range of pheniramine. Further increase in the activity on the atrium was achieved by disubstitution with halogen on the phenyl ring, such as 3,4-F2, 3,5-F2, and 3,4-Cl2 (63-65). The 2-pyridyl group in arpromidine was replaced by 3-pyridyl without significant change in H2 agonistic activity, whereas the 4-pyridyl and phenyl analogues were less active. The rank order of potency in the atrium was in good agreement with the positive inotropic effects found in isolated, perfused guinea pig hearts, where 63-65 were the most potent compounds as well.

Animals↗
PubMed1987

[Synthesis and pharmacologic action of substituted imidazolyl- and thiazolylmethylthioethylguanidine].

Starting with diphenyl N-benzoyl-carbonimidate impromidine analogues characterized by various substituted imidazole or thiazole groups instead of the 5-methylimidazole part have been synthesized and tested for H2-agonistic and H1-antagonistic activity as well. The most potent substances 6h,i are 20-30 times more active than histamine at the H2-receptors in the isolated spontaneously beating guinea-pig right atrium. In isolated perfused guinea-pig hearts 6h,i were found to predominantly stimulate heart rate, whereas the increase in LVdp/dtmax was about 40% of impromidine's maximal response.

Animals↗
PubMed1987

[Synthesis and pharmacologic action of arylmethylethylguanidines].

Impromidine analogous guanidines have been prepared characterized by H2-unspecific arylmethyl groups instead of the 5-methylimidazole residue. The most potent substances proved to be about 20 times more active than histamine at the isolated spontaneously beating guinea-pig right atrium (H2-agonism), simultaneously showing moderate H1-antagonistic activity at the guinea-pig ileum. In isolated perfused guinea-pig hearts the thenylthioethylguanidine 9e was very potent in increasing LVdp/dtmax, achieving about 90% of impromidine's maximal response. In comparison with impromidine the increase in heart rate was lower and rhythm disturbances were substantially reduced.

Animals↗