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Biomedical subjects

H Timmerman

Publications and source records attributed to H Timmerman.

263 records · Page 15Linked to original sources
PubMedDate not supplied

Binding of clozapine metabolites and analogues to the histamine H3 receptor in rat brain cortex.

Following up the finding that the non-imidazole drug clozapine shows a considerable histamine H3 receptor antagonistic activity, a series of analogues and metabolites (clozapine-N-oxide, and N-desmethylclozapine) were tested for their affinity towards the H3 receptor using the radiolabelled H3 antagonist [125I]-iodophenpropit. Qualitative structure affinity relationships are derived for the tested compounds. In the clozapine molecule four structurally different moieties may be considered. In comparison with the affinity for the H3 receptor shown by clozapine, the following main conclusions can be drawn: The 4-piperazinyl region does not allow substituents longer than a CH3 or electronegative atoms such as an O (as in clozapine-N-oxide); the lack of the CH3 group (as in N-desmethylclozapine) also reduces the affinity for H3 receptors. Substitutions at the 5-diazepine position do not drastically alter the affinity for the H3 receptor, although a basic nitrogen is favoured over CH2, O, or S. The 8 position in ring I is an important modulatory site for H3 affinity; electronegative substituents such as chloro and fluoro in this aromatic ring increase the affinity. When these substituents are, however, present at position X2 in the ring, they disable binding to the H3 receptor. The two major clozapine metabolites (clozapine-N-oxide, and N-desmethylclozapine) will not be responsible for a possible contribution of the H3 receptor antagonism to the clinical profile of clozapine.

Animals↗
PubMedDate not supplied

Histamine H1 receptor ligands: part II. Synthesis and in vitro pharmacology of 2-[2-(phenylamino)thiazol-4-yl]ethanamine and 2-(2-benzhydrylthiazol-4-yl)ethanamine derivatives.

New 2-[2-(phenylamino)thiazol-4-yl]ethanamine and 2-(2-benzhydrylthiazol-4-yl)ethanamine derivatives were prepared and tested in vitro as H1 receptor antagonists. The compounds with 2-phenylamino substitution with meta-halide substituents at the phenyl ring, showed weak H1-antagonistic activity (pA2: 4.62-5.04) and this activity was completely lost in the case of meta-methyl substituent (pA2 < 4). When the phenylamino group was replaced by benzhydryl groups of classic antihistamines, the resulting compounds exhibited slightly improved H1-antagonistic activity (at the meta-position pA2: 6.38-6.15; at the para-position pA2: 6.04-5.87).

Animals↗
PubMedDate not supplied

Comparison of the in vivo effects of morphine and methadone on natural killer cell activity in spleen, peritoneal cavity, and lungs in rats.

Opiates and opioid agents are known to affect the immune system. In humans this includes alterations in natural killer (NK) cell activity. Morphine is reported to reduce in vivo spleen NK activity in rats, whereas for methadone only in vitro data have been described. In the present paper we describe a systematic study on the chronic effects of well-known opiates, comparing for the first time the effects of morphine and methadone on NK cell activity in various organs: in addition to spleen, also in the peritoneal cavity, and lungs. In all organs the NK activity was determined using three effector: target cell ratios. Morphine and methadone given by food during 6 weeks decreased the NK cell activity in rat spleen, supporting published data on morphine. The role of the opiate receptor is discussed. However, the overall action of morphine could not be described as suppressive because stimulation of NK cell activity in the peritoneal cavity and lungs by morphine was found. In contrast, methadone induced a decrease in the NK cell activity in these organs. Apart from these differential expressions of morphine- and methadone associated effects on NK cell activity, the findings demonstrate the potential adverse effects of these opiates on an important antiviral defence mechanism.

Animals↗
PubMedDate not supplied

Influence of membrane composition of various parasites on the inhibitory activity of a series of bipyridyl analogues.

In a previous report the dependence of the antimycoplasmal activity of bipyridyl analogues on the presence of Cu+ ions has been shown. The inhibitory activity of these compounds has now been studied against Escherichia coli mycobacteria and Candida albicans in the absence and presence of Cu2+ ions using growth kinetic techniques. It was found that the inhibitory activity against E. coli increases in the presence of Cu2+ ions. In contrast, no additional effect of Cu2+ ions is observed for the inhibitory activity against mycobacteria. Some of the derivatives show very promising activity even against Mycobacterium avium strains. More complicated is the effect of Cu2+ ions on the inhibitory activity of the derivatives against C. albicans. For isoquinolones the observed delay in onset of inhibitors is reduced and no influence on the inhibitory activity is observed. The addition of Cu2+ ions to the phenanthrolines leads in contrast to a decrease in antifungal activity. The possible influence of membrane properties of the studied microorganism on the effect of Cu2+ ions is discussed.

2,2'-Dipyridyl↗
PubMedDate not supplied

Studies on histaminergic compounds, Part VII. Histamine H2-binding on guinea-pig cerebral cortex compared to histamine (ant)agonism.

The pKD values of series of H2-active compounds, obtained from displacement curves of 3H-tiotidine from a guinea-pig cerebral cortex homogenate were compared with the pA2/pD2 values of these compounds on the right atrium of the same animal species. A good correlation was found between the cortex pKD value and the pharmacological activity on the right atrium, especially with the antagonists, the partial agonists and the agonistic impromidine analogues (guanidines). The poor correlation between cortex pKD and atrium pD2 of some other agonists (the amines) might be explained by the presence of spare receptors for these compounds. The different number of spare receptors for the guanidines and the amines might be explained by the differences in base strength of these compounds.

Animals↗
PubMedDate not supplied

Desensitization of guinea-pig parenchymal lung strips after prolonged histamine H1-receptor stimulation.

In this study we examined the desensitization of guinea-pig parenchymal lung strips after excessive stimulation of the histamine H1-receptor. After stimulation with maximal effective concentrations of the selective H1-receptor agonist 2-pyridylethylamine (1 mM) for 30 min, subsequent 2-pyridylethylamine responses were inhibited as shown in a depression of the maximal response with approximately 40%. This desensitization was time- and concentration-dependent. Besides H1-receptor responses, potassium chloride (50 mM)-induced responses were also affected. Treatment of lung strips with 1 mM of 2-pyridylethylamine for 30 min resulted in an inhibition of the potassium-induced contraction with 26.1 +/- 8.7% of the control response. Desensitization of the lung strip preparation could not be prevented by the cyclooxygenase inhibitor indomethacin (20 microM), indicating that the observed inhibition is not due to an elevated production of relaxing prostaglandins. Desensitization was also not dependent on the influx of extracellular calcium. Stimulation of guinea-pig parenchymal lung strips with 1 mM of 2-pyridylethylamine in a calcium-free buffer, supplemented with the calcium chelator EGTA, did not lead to observable contractions. However, desensitization still developed under these conditions. These data indicate that guinea-pig parenchymal lung strips exhibit a desensitized state after prolonged H1-receptor stimulation. Because this effect is not only limited to H1-receptor responses, as KCl effects are reduced as well, it should, at least partly, be explained by an interference with processes which occur distally to the H1-receptor itself.

Animals↗
PubMedDate not supplied

Beta-adrenoceptor agonists do not reduce hydrogen peroxide production from superoxide radicals.

Recently, it has been reported that beta-adrenoceptor agonists containing a catechol moiety, reduce hydrogen peroxide production by alveolar macrophages, an effect suggested to be due to scavenging by the catecholamines of superoxide, the precursor of hydrogen peroxide. However, catecholamines interfere with the method used, in that study, to determine hydrogen peroxide formation. We re-examined the obtained results using two independent methods for measuring hydrogen peroxide that are not affected by catecholamines. We found that catecholamines, in a concentration up to 10(-5) M, had no effect on hydrogen peroxide formation out of superoxide. It was, furthermore, established that reduction of hydrogen peroxide formation by scavenging of superoxide by catecholamines is not very likely.

Adrenergic beta-Agonists↗