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Biomedical subjects

H Timmerman

Publications and source records attributed to H Timmerman.

At least 127 records · Page 7Linked to original sources
PubMed1995

Modelling and mutation studies on the histamine H1-receptor agonist binding site reveal different binding modes for H1-agonists: Asp116 (TM3) has a constitutive role in receptor stimulation.

A modelling study has been carried out, investigating the binding of histamine (Hist), 2-methylhistamine (2-MeHist) and 2-phenylhistamine (2-PhHist) at two postulated agonistic binding sites on transmembrane domain 5 (TM5) of the histamine H1-receptor. For this purpose a conformational analysis study was performed on three particular residues of TM5, i.e., Lys200, Thr203 and Asn207, for which a functional role in binding has been proposed. The most favourable results were obtained for the interaction between Hist and the Lys200/Asn207 pair. Therefore, Lys200 was subsequently mutated and converted to an alanine, resulting in a 50-fold decrease of H1-receptor stimulation by histamine. Altogether, the data suggest that the Lys200/Asn207 pair is important for activation of the H1-receptor by histamine. In contrast, analogues of 2-PhHist seem to belong to a distinct subclass of histamine agonists and an alternative mode of binding is proposed in which the 2-phenyl ring binds to the same receptor location as one of the aromatic rings of classical histamine H1-antagonists. Subsequently, the binding modes of the agonists Hist, 2-MeHist and 2-PhHist and the H1-antagonist cyproheptadine were evaluated in three different seven-alpha-helical models of the H1-receptor built in homology with bacteriorhodopsin, but using three different alignments. Our findings suggest that the position of the carboxylate group of Asp116 (TM3) within the receptor pocket depends on whether an agonist or an antagonist binds to the protein; a conformational change of this aspartate residue upon agonist binding is expected to play an essential role in receptor stimulation.

Amino Acid Sequence↗
PubMed1995

Cardiovascular effects of selective agonists and antagonists of histamine H3 receptors in the anaesthetized rat.

The cardiovascular responses to a series of selective histamine H3 receptor agonists, (R) alpha-methylhistamine, imetit and immepip and selective antagonists, thioperamide, clobenpropit and clophenpropit, were studied in anaesthetized rats. At 0.003-1 mumol/kg i.v. doses, H3 agonists failed to produce any significant change in the basal blood pressure and heart rate. Larger doses of (R) alpha-methylhistamine increased the blood pressure and heart rate and higher doses of imetit caused vasodepressor responses and reduced heart rate, whereas immepip proved virtually inactive. While (R) alpha-methylhistamine-induced effects were not blocked by histamine H1-, H2- and H3-receptor antagonists, they were however reduced by idazoxan and propranolol, which indicates that the mechanisms involved are adrenergic. The effects induced by imetit are not related to histamine H3 receptors but are mediated by indirect (via 5HT3 receptors) cholinergic mechanisms, since these effects were prevented by 1 mg/kg i.v. atropine and by 0.1 mg/kg i.v. ondansetron. Similarly, the H3 antagonists per se failed to change basal cardiovascular function up to 10 mumol/kg i.v. and only at 30 mumol/kg i.v. were marked decreases observed in the blood pressure and heart rate with a significant reduction in the effects of noradrenaline. These data indicate that in anaesthetized rats, histamine H3 receptor activation or blockade has no effect on basal cardiovascular function. The effects recorded after the administration of large doses of (R) alpha-methylhistamine and imetit are clearly unrelated to histamine H3 receptors and should be taken into account when using these compounds as H3 ligands for "in vivo" experiments.

Analysis of Variance↗
PubMed1995

Molecular pharmacological aspects of histamine receptors.

In this article, we review the recent developments in the field of histamine research. Besides the description of pharmacological tools for the H1, H2 and H3 receptor, specific attention is paid to both the molecular aspects of the receptor proteins, including the recent cloning of the receptor genes, and their respective signal transduction mechanisms.

Amino Acid Sequence↗
PubMed1995

Does the ternary complex act as a secondary proton pump and a GTP synthase?

It has been suggested that G protein-coupled receptors can act as proton transporters, with the activated G protein-coupled receptor transporting H+ across the membrane from the extracellular side to the cytoplasm. In this article, Paul Nederkoorn, Henk Timmerman and Gabriëlle Donné-Op den Kelder summarize the various H+ translocation mechanisms and how these compare with activated G protein-coupled receptors. The G protein, being part of the ternary complex, is proposed to use translocated protons to synthesize GTP from GDP and Pi, thus functioning in a similar manner to ATP synthase. The importance of these events in physiological effects such as signal amplification is discussed.

GTP-Binding Proteins↗
PubMed1995

Interaction of clozapine with the histamine H3 receptor in rat brain.

We examined possible interactions between neuroleptics and the histamine H3 receptor and found an interaction of clozapine with this receptor. In competition binding experiments, using the H3 antagonist, [125I]-iodophenpropit, we observed a Ki of 236 +/- 87 nM. Functionally, clozapine was studied on the H3-mediated inhibition of [3H]-5-hydroxytryptamine ([3H]-5-HT) release from rat brain cortex slices. Clozapine acts as an antagonist with an apparent KB value of 79.5 nM.

Animals↗
PubMed1995

Evaluation of the receptor selectivity of the H3 receptor antagonists, iodophenpropit and thioperamide: an interaction with the 5-HT3 receptor revealed.

1. In the present study we evaluated the receptor selectivity of the potent histamine H3 receptor antagonist, iodophenpropit (IPP) in comparison with the prototype antagonist, thioperamide. 2. IPP proved to be a potent competitive H3 receptor antagonist as measured against (R)-alpha-methylhistamine-induced inhibition of electrically-evoked contractions of the guinea-pig jejunum (pA2 = 9.12 +/- 0.06, Schild slope: 1.0 +/- 0.1, n = 8). In the same assay, thioperamide was slightly less potent (pA2 = 8.9 +/- 0.2). 3. In radioligand binding studies, IPP showed a high affinity for the H3 receptor. Displacement of [125I]-IPP binding to rat cortex membranes by unlabelled IPP resulted in a Ki value of 0.97 +/- 0.06 nM (n = 3). In contrast, IPP showed only a weak affinity for the histamine H1- and H2 receptor. Displacement of [3H]-mepyramine and [125I]-iodoaminopotentidine binding to respectively guinea-pig H1- and human H2 receptors by IPP resulted in Ki values of 1.71 +/- 0.32 microM (n = 3) and 2.28 +/- 0.81 microM (n = 3). For thioperamide the affinities for the H1-, H2- and H3 receptor were respectively > 10 microM, > 10 microM and 4.3 +/- 1.6 nM (n = 7). 4. Testing IPP and thioperamide in 39 different receptor binding assays revealed that IPP showed relatively high affinity for the 5-hydroxytryptamine 5-HT3 receptor (Ki = 11 +/- 1 nM, n = 3), the alpha 2-adrenoceptor (Ki = 120 +/- 5 nM, n = 3) and the sigma receptor (Ki = 170 +/- 70 nM, n = 3). Thioperamide showed relatively high affinity for the 5-HT3 receptor (Ki = 120 +/- 30 nM, n = 3) and the sigma receptor (Ki = 180 +/- 90 nM, n = 3). 5. Due to the low density of histamine H3 receptors in the brain, the interaction of IPP with the 5-HT3-, the alpha 2- and the sigma receptor might interfere with [125I]-IPP binding to rat cortex membranes. Yet, in this preparation [125I]-IPP binding was not influenced by ondansetron, yohimbine or haloperidol. The interaction with the 5-HT3 receptor was not restricted to IPP or thioperamide, but was alsofound with other H3 receptor antagonists. The potent H3 receptor agonist imetit, a compound belongingto the same chemical class of IPP, also interacted with the 5-HT3 receptor (Ki = 240 +/- 40 nM). In contrast,histamine or the H3 receptor agonist, (R)-a-methylhistamine showed no affinity for the 5-HT3 receptor.7 In the guinea-pig isolated ileum, imetit evoked concentration-dependent contractions, resulting in apD2 value of 4.72 +/- 0.03 (n = 9). The contractions were antagonized by ondansetron, yielding a pA2 valueof 7.1 +/- 0.1 (n = 9). Similarly ondansetron antagonized the contractions evoked by the 5-HT3 receptoragonist, 2-methyl-5-HT with a pA2 value of 7.3 +/- 0.1 (n = 4). IPP and thioperamide did not mimic 2-methyl-5-HT but non-competitively inhibited the 2-methyl-5-HT-induced contractions of thispreparation.8 In an in vivo model for 5-HT3 activity, the Von Bezold Jarisch reflex, thioperamide showedantagonism in low dosages, which correlated well with the affinity for the 5-HT3 receptor site. Yet, athigher dosages no further 5-HT3 receptor antagonism was observed. For IPP no 5-HT3 receptor activitycould be observed in vivo.9 In the present study we showed that many H3 receptor compounds, that are regarded as highlyselective (including the prototype drug, thioperamide), also interact with the 5-HT3 receptor, albeit athigher drug concentrations.Keywords.: Histamine H3-receptor; iodophenpropit; thioperamide; receptor selectivity; 5-hydroxytryptamine 5-HT3 receptor;guinea-pig intestine; rat brain; Von Bezold Jarisch reflex

Animals↗
PubMed1994

Rapid desensitization of the histamine H2 receptor on the human monocytic cell line U937.

In the present study we have subjected the histamine H2 receptor on the monocytic cell line U937 to a thorough pharmacological characterization using a series of selective histamine H1, H2 and H3 receptor agonists and antagonists. Recent reports have demonstrated the existence of a histamine H2 receptor on HL-60 and HGT-1 cells with a pharmacological profile distinct from the commonly described histamine H2 receptor. U937 cells, however, seem to express classical histamine H2 receptors. Histamine and dimaprit dose dependently induce the formation of cAMP, whereas dimaprit's inactive analogues, nordimaprit and homodimaprit, show reduced potencies. Histamine H1 and H3 receptor agonists do not show histamine H2 receptor activity. Various histamine H2 receptor antagonists are able to block the histamine induced production of cAMP with an antagonistic profile comparable to that observed in the guinea-pig right atrium. Furthermore, endogenous histamine H2 receptors in U937 cells are found to be susceptible to receptor desensitization, a mechanism which may become apparent under pathophysiological conditions or during drug therapy. A 30-min pre-exposure of U937 cells to histamine (100 microM) results in a 50% attenuation of the production of cAMP to a subsequent application of an agonist. Desensitization of the histamine H2 receptor in U937 cells is found to be homologous as the beta-adrenoceptor mediated response remained unaffected.

Cells, Cultured↗
PubMed1994

Clobenpropit (VUF-9153), a new histamine H3 receptor antagonist, inhibits electrically induced convulsions in mice.

The effect of clobenpropit (VUF-9153), a new histamine H3 receptor antagonist, on electrically induced convulsions was studied in mice. Clobenpropit significantly and dose dependently decreased the duration of each convulsive phase. Its anticonvulsant effects were prevented by pretreatment with (R)-alpha-methylhistamine and imetit (VUF-8325), histamine H3 receptor agonists. These findings suggest that the effect of clobenpropit on electrically induced convulsions is due to an increase in endogenous histamine release in the brain, which is consistent with biochemical results that clobenpropit increased brain histidine decarboxylase activity dose dependently. The anticonvulsive effect of clobenpropit was antagonized by mepyramine, a histamine H1 receptor antagonist, but not by zolantidine, a histamine H2 receptor antagonist, indicating that histamine released by the anticonvulsant effect of clobenpropit interacts with histamine H1 receptors of postsynaptic neurons. The present findings of the effect of clobenpropit on electrically induced convulsions are fully consistent with those of thioperamide as described previously (Yokoyama et al., 1993, Eur. J. Pharmacol. 234, 129), supporting the hypothesis that the central histaminergic neuron system is involved in the inhibition of seizures.

Animals↗
PubMed1994

Site-directed mutagenesis of the histamine H1-receptor reveals a selective interaction of asparagine207 with subclasses of H1-receptor agonists.

In this study we investigated the role of the threonine203 and the asparagine207 residues in the fifth transmembrane domain of the guinea-pig histamine H1-receptor by site-directed mutagenesis to non-functional alanines. Whereas the threonine203 residue is not important for the action of histamine, the asparagine207 residue appears to be involved in the binding of the N tau-nitrogen atom of histamine and its 2-methyl-analogue. For the 2-phenyl-analogue and non-imidazole H1-receptor agonists, this residue is, however, not essential for binding. On the basis of this study we conclude that different histamine H1-receptor agonists interact in different ways with the H1-receptor protein. Moreover, we speculate that the interaction with the N pi-nitrogen atom is essential for H1-receptor activation.

Animals↗
PubMed1994

Optically active analogues of ebastine: synthesis and effect of chirality on their antihistaminic and antimuscarinic activity.

A series of optically active analogues of the H1-antihistamine ebastine, with chiral center(s) at the benzhydryl and/or phenylbutyl part of the molecule, have been synthesized. Their in vitro antihistaminic and antimuscarinic activities were investigated, along with a molecular modelling study. It was found that introduction of the benzhydryl chiral center yielded significant stereoselectivity for both antihistaminic and antimuscarinic activities. The steric preferences of the benzhydryl chiral center for antihistaminic and antimuscarinic actions were mirror images of each other. The (-)-isomer of 4-methylebastine (6d) showed more than 10-fold higher in vitro antihistaminic potency than ebastine. Meanwhile the selectivity of 6d for histamine H1-receptors was also increased by more than 20 times in comparison with ebastine. The chirality at the phenylbutyl part of the molecule does not significantly alter the antihistaminic or antimuscarinic activity of the compounds although the (S)-isomers showed slightly but unanimously higher antihistaminic activity than the (R)-isomers. These results have been discussed with existing stereoselectivity data of antihistamines and an asymmetric pharmacophore model for H1-antagonists has been described.

Animals↗
PubMed1994

The involvement of nitric oxide synthase in the effect of histamine on guinea-pig airway smooth muscle in vitro.

The influence of histamine on nitric oxide synthase (NOS) in the development of airway smooth muscle hyperresponsiveness to histamine was investigated in vitro. In the absence of histamine, NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) had no significant effect on the basal tone. However, precontraction of the tissues with histamine (0.3 microM) resulted in a significant contractile response to L-NAME in the preparations with intact epithelium. Removal of the epithelial layer decreased the responses to L-NAME. L-arginine could partially reverse the contraction produced by L-NAME. L-NAME enhanced the maximal response to histamine, but the sensitivity of the tracheal smooth muscle to histamine was not affected. These results suggest that, in the airway, histamine can activate NOS, resulting in the release of nitric oxide. The latter may be regarded as a local negative modulator to maintain the tissue in a physiological homeostasis.

Amino Acid Oxidoreductases↗
PubMed1994

Chiral manipulation of drug selectivity: studies on a series of terfenadine-derived dual antagonists on H1-receptors and calcium channels.

A series of terfenadine derivatives were evaluated for enantioselectivity on histamine H1-receptors and calcium channels. Whereas H1-receptors are only sterically discriminative against the benzhydryl part of the molecules, calcium channels showed enantioselectivity to either the phenylbutyl part or the benzhydryl part provided that an appropriate lipophilicity is preserved at the chiral site. It is speculated that the hydrophilicity of the butanol moiety is responsible for the lack of stereoselectivity of terfenadine enantiomers since it drives the side chain out of the stereoselective site of calcium channels, which are lipophilic. In four different test systems, (guinea-pig ileum, guinea-pig lung membranes, rat aorta and rat cortex membranes), this series of compounds generally showed about 10 times higher activity on H1-receptors than on calcium channels. By introducing a chiral center in the different parts of the molecule we were able to increase the selectivity of an enantiomer VUF4648 to calcium channels.

Animals↗
PubMed1994

A new model for the agonistic binding site on the histamine H2-receptor: the catalytic triad in serine proteases as a model for the binding site of histamine H2-receptor agonists.

The historical model for the agonistic binding site on the histamine H2-receptor is based on a postulated activation mechanism: it has been suggested that the histamine monocation binds to the histamine H2-receptor via the formation of three hydrogen bonds. The cationic ammonium group in the side chain and the -NH- group in the tau-position of the imidazole act as proton donors, whereas the =N- atom in the pi-position of the imidazole acts as a proton acceptor. Participation of the ammonium group in H-bonding with a presumed negative charge on the receptor leads to a decrease in positive charge, which is thought to induce a tautomeric change in the imidazole ring system from N tau-H to N pi-H. A consequence of this tautomeric shift is the donation of a proton from the receptor to the agonist on one side, while on the other side a proton is donated from the agonist to the receptor. The propose tautomeric shift has been suggested to trigger the H2-stimulating effect. However, this model for the constitution of the agonistic binding site and the accessory activation mechanism cannot explain the weak histamine H2-activity of beta-histine and the activity of several other recently synthesized H2-agonists. Based on a thorough literature study and with the aid of molecular electrostatic potentials (MEPs) we demonstrate that the sulphur atom present in histamine H2-agonists as dimaprit and 2-amino-5-(2-aminoethyl)thiazole does not function as a proton acceptor, which implicitly means that a tautomeric shift is not a prerequisite for H2-stimulation. As a consequence, the model for the agonistic binding site is adjusted, resulting in a strong resemblance to the nature and orientation of the amino acids constituting the catalytic triad in serine proteases. Within this concept, the N pi-H tautomer of histamine is the biologically active form, in contrast with the existing model in which the N tau-H tautomer is the active form.

Animals↗