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Biomedical subjects

H Timmerman

Publications and source records attributed to H Timmerman.

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

Characterization of histamine H3 receptors in mouse brain using the H3 antagonist [125I]iodophenpropit.

We have characterized the binding of the histamine H3 receptor antagonist [125I]iodophenpropit to mouse brain. [125I]Iodophenpropit saturably bound to mouse brain membranes with a pKd-value of 9.31+/-0.04 nM and a receptor binding density of 290+/-8 fmol per mg protein. Saturation binding analysis revealed binding of [125I]iodophenpropit to a single class of sites, showing linear Scatchard plots and Hill coefficients not different from unity (nH=0.98+/-0.02). At a concentration of 0.25 nM [125I]iodophenpropit, specific binding represented about 75% of the total binding. Competition binding curves for H3 receptor antagonists were fitted best to a one-site model, showing pKi-values in general accordance with the pA2-values obtained in mouse cerebral cortex. Displacement of [125I]iodophenpropit by the H3 receptor agonists (R)-alpha-methylhistamine, immepip, imetit and histamine were fitted best to a two-site model. Competition binding curves of (R)-alpha-methylhistamine showed a rightward shift upon incubation with GTPgammaS (10 microM), indicating the involvement of G-proteins in H3 agonist binding. In contrast, competition binding curves of the antagonists iodophenpropit, thioperamide and burimamide were not affected by GTPgammaS (10 microM). Autoradiographic experiments showed that [125I]iodophenpropit binding sites were heterogeneously distributed, similarly to the distribution of histamine H3 receptors reported in rat brain. Highest densities were observed in the cerebral cortex, the striatum, the nucleus accumbens, the globus pallidus and the substantia nigra. In conclusion, we have demonstrated that in mouse brain, [125I]iodophenpropit selectively binds to histamine H3 receptors. We also observed that the mouse brain H3 receptors labelled by [125I]iodophenpropit displayed binding characteristics and a distribution similar to rat brain.

Animals↗
PubMed2000

Is histamine the final neurotransmitter in the entrainment of circadian rhythms in mammals?

Adaptation of circadian rhythms to the environmental light-dark cycle is necessary for the survival of organisms. This synchronization or entrainment is only caused by light (photic input) during the dark period, according to the internal biological clock of an organism. During the light period, internal factors (non-photic input), rather than light, are able to entrain circadian rhythms. In this article, the data that implicate the neurotransmitter system for histamine in circadian entrainment are reviewed. Furthermore, we speculate that histamine receptors are the final gate at which both photic and non-photic entrainment mechanisms converge before sending a resetting signal to the intracellular biological clock.

Animals↗
PubMed2000

Selective ligands as tools to study histamine receptors.

In this review the histaminergic ligands for the histamine H(1), H(2) and H(3) receptors, which are currently used as tools in pharmacological studies, are described. To study interactions with the histamine H(1) receptor, the H(1) agonist 2-aminoethylthiazole has long since been used. However, during the last decade, 2-phenylhistamine derivatives emerged with interesting binding features. So far no radiolabelled selective H(1) agonist has been commonly used. As H(1) antagonists mepyramine, triprolidine and chlorpheniramine are described together with radiolabelled H(1) antagonists [3H]mepyramine and [3H]doxepin. Special attention has been paid to the PET ligands [11C]doxepin and [11C]mepyramine and the [125I] labelled antagonists [125I]iodobolpyramine and [125I]iodoazidophenpyramine. Concerning H(2) agonists, especially dimaprit, amthamine and impromidine are discussed. There are several H(2) antagonists; amongst them cimetidine, tiotidine and ranitidine are used most frequently. Many of these antagonists behave as inverse agonists. As radiolabelled H(2) antagonists, [3H]cimetidine, [3H]tiotidine, [125I]iodoaminopotentidine and [125I]iodoazidopotentidine are included. Commonly used histamine H(3) agonists are N(alpha)-methylhistamine, (R)alpha-methylhistamine, imetit and immepip. Both methylhistamines are also available as [3H] labelled ligands. As reference compounds, often used H(3) antagonists are thioperamide, clobenpropit, iodophenpropit and impentamine. Most important radiolabelled H(3) antagonists are S-[3H]methylthioperamide, [3H]thioperamide, [125I]iodophenpropit and [125I]iodoproxyfan. The use of all these compounds as a tool in pharmacology is also discussed.

Animals↗
PubMed2000

Synthesis of benzylideneacetophenones and their inhibition of lipid peroxidation.

A series of benzylideneacetophenone derivatives have been synthesized and found to show potent inhibition of the lipid peroxidation (LPO) in rat liver microsomes. All 19 compounds prepared in this series are LPO inhibitors. The highest activity was found in para hydroxy derivatives with two meta tert-butyl substituents.

Acetophenones↗
PubMed2000

Modulation of histamine H(2) receptor signalling by G-protein-coupled receptor kinase 2 and 3.

To evaluate the role of G-protein-coupled receptor kinases (GRK) in the desensitization of the histamine H(2) receptor, the H(2) receptor was transiently cotransfected with GRK2, 3, 5 or 6 in COS-7 cells and the cyclic AMP levels in response to histamine were studied. Coexpression of the H(2) receptor with GRK2 and 3 significantly decreased both the basal cyclic AMP levels and the cyclic AMP response to 100 microM histamine. Moreover, preincubation with 100 microM histamine desensitized the H(2) receptor response to 53+/-8%. Coexpression of GRK2 and 3 increased the H(2) receptor desensitization to 27+/-4% and 24+/-4% respectively. No effect on either cyclic AMP response or desensitization was found when GRK5, GRK6 or dominant negative mutants of GRK2 or 3 (GRK2K(220)R and GRK3K(220)R) were coexpressed. To study the role of the C-terminal tail in the GRK-mediated desensitization of the H(2) receptor, three truncations of C-tail were constructed: H(2)T295, H(2)T307 and H(2)T341. H(2)T307 and 341 H(2)T341 expressed and responded normally to 100 microM histamine. The interaction of the H(2) receptor with GRK2 and 3 was also not altered upon truncation of the C-terminal tail. These findings strongly suggest a role of GRK2 and 3 in the desensitization of the H(2) receptor. Furthermore, the finding that C-terminal truncations of the H(2) receptor did not abolish the effect of GRK2 and 3 suggests that the C-terminus is not involved in the GRK mediated desensitization of the histamine H(2) receptor.

Amino Acid Sequence↗
PubMed2000

A third life for burimamide. Discovery and characterization of a novel class of non-opioid analgesics derived from histamine antagonists.

Burimamide, a histamine (HA) derivative with both H2- and H3-blocking properties, induces antinociception when injected into the rodent CNS. Several related compounds share this property, and structure-activity studies have shown that this new class of analgesics is distinct from known HA antagonists. The prototype, named improgan, shows a preclinical profile of a highly effective analgesic, with activity against thermal, mechanical and inflammatory nociception after doses that do not alter motor balance or locomotor activity. Improgen analgesia is not blocked by opioid antagonists and is observed in opioid receptor knock-out mice. Unlike morphine, improgan does not induce tolerance after daily dosing. Extensive in vitro pharmacology studies have excluded known histaminergic, opioid, serotonergic, GABAergic and adrenergic receptor mechanisms, as well as 50 other sites of action. The improgan-like analgesic activity of some HA congeners suggests an analgesic action on a novel HA receptor, but further studies are required to substantiate this. Studies in progress are characterizing the sites and mechanisms of action of improgan, and developing brain-penetrating derivatives that could be useful for clinical pain.

Analgesics, Non-Narcotic↗
PubMed2000

The effect of mutations in the DRY motif on the constitutive activity and structural instability of the histamine H(2) receptor.

In previous studies we showed that the wild-type histamine H(2) receptor stably expressed in Chinese hamster ovary cells is constitutively active. Because constitutive activity of the H(2) receptor is already found at low expression levels (300 fmol/mg protein) this receptor is a relatively unique member of the G-protein-coupled receptor (GPCR) family and a useful tool for studying GPCR activation. In this study the role of the highly conserved DRY motif in activation of the H(2) receptor was investigated. Mutation of the aspartate 115 residue in this motif resulted in H(2) receptors with high constitutive activity, increased agonist affinity, and increased signaling properties. In addition, the mutant receptors were shown to be highly structurally instable. Mutation of the arginine 116 residue in the DRY motif resulted also in a highly structurally instable receptor; expression of the receptor could only be detected after stabilization with either an agonist or inverse agonist. Moreover, the agonist affinity at the Arg-116 mutant receptors was increased, whereas the signal transduction properties of these receptors were decreased. We conclude that the Arg-116 mutant receptors can adopt an active conformation but have a decreased ability to couple to or activate the G(s)-protein. This study examines the pivotal role of the aspartate and arginine residues of the DRY motif in GPCR function. Disruption of receptor stabilizing constraints by mutation in the DRY motif leads to the formation of active GPCR conformations, but concomitantly to GPCR instability.

Amino Acid Motifs↗
PubMed1999

Non-imidazole histamine H3 ligands. Part I. Synthesis of 2-(1-piperazinyl)- and 2-(hexahydro-1H-1,4-diazepin-1-yl)benzothiazole derivatives as H3-antagonists with H1 blocking activities.

New 2-(1-Piperazinyl)- and 2-(hexahydro-1H-1,4-diazepin-1-yl)benzothiazoles were prepared and tested as H1- and H3-receptor antagonists. A number of compounds showed weak H1-antagonistic activity, with pA2 values ranging from 5.5 to 6.1. The simple alkyl substituted, 2-[1-(4-methyl and 4-ethyl)piperazinyl] analogues show increasing, moderate H3-antagonistic activity (pA2 = 6.0, and pA2 = 7.0). The compounds with 4-phenylalkyl substitution, for both the piperazinyl and the hexahydro-1H-1,4-diazepin-1-yl homologues series, regardless of the different physicochemical properties of the para substituents at the phenyl ring, showed weak H3-antagonistic activity with pA2 values ranging from 4.4 to 5.6.

Animals↗
PubMed1999

Mutational analysis of the antagonist-binding site of the histamine H(1) receptor.

We combined in a previously derived three-dimensional model of the histamine H(1) receptor (Ter Laak, A. M., Timmerman, H., Leurs, H., Nederkoorn, P. H. J., Smit, M. J., and Donne-Op den Kelder, G. M. (1995) J. Comp. Aid. Mol. Design. 9, 319-330) a pharmacophore for the H(1) antagonist binding site (Ter Laak, A. M., Venhorst, J., Timmerman, H., and Donné-Op de Kelder, G. M. (1994) J. Med. Chem. 38, 3351-3360) with the known interacting amino acid residue Asp(116) (in transmembrane domain III) of the H(1) receptor and verified the predicted receptor-ligand interactions by site-directed mutagenesis. This resulted in the identification of the aromatic amino acids Trp(167), Phe(433), and Phe(436) in transmembrane domains IV and VI of the H(1) receptor as probable interaction points for the trans-aromatic ring of the H(1) antagonists. Subsequently, a specific interaction of carboxylate moieties of two therapeutically important, zwitterionic H(1) antagonists with Lys(200) in transmembrane domain V was predicted. A Lys(200) --> Ala mutation results in a 50- (acrivastine) to 8-fold (d-cetirizine) loss of affinity of these zwitterionic antagonists. In contrast, the affinities of structural analogs of acrivastine and cetirizine lacking the carboxylate group, triprolidine and meclozine, respectively, are unaffected by the Lys(200) --> Ala mutation. These data strongly suggest that Lys(200), unique for the H(1) receptor, acts as a specific anchor point for these "second generation" H(1) antagonists.

Animals↗
PubMed1999

Histamine H1 receptor ligands. Part I. Novel thiazol-4-ylethanamine derivatives: synthesis and in vitro pharmacology.

A series of 2-substituted thiazol-4-ylethanamines have been synthesized and tested for their histaminergic H1-receptor activities. The compounds with 2-phenyl substitution, regardless of the different physicochemical properties of the meta-substituents at the phenyl ring, showed weak H1-agonistic activity with pD2 values ranging from 4.35 to 5.36. When the phenyl group was replaced by a benzyl group, the resulting compounds all exhibited weak H1-antagonistic activity (pA2: 4.14-4.82).

Animals↗
PubMed1999

Characterization of the binding site of the histamine H3 receptor. 1. Various approaches to the synthesis of 2-(1H-imidazol-4-yl)cyclopropylamine and histaminergic activity of (1R,2R)- and (1S,2S)-2-(1H-imidazol-4-yl)-cyclopropylamine.

Various approaches to the synthesis of all four stereoisomers of 2-(1H-imidazol-4-yl)cyclopropylamine (cyclopropylhistamine) are described. The rapid and convenient synthesis and resolution of trans-cyclopropylhistamine is reported. The absolute configuration of its enantiomers was determined by single-crystal X-ray crystallographic analysis. The distinct trans-cyclopropylhistamine enantiomers were tested for their activity and affinity on the histamine H3 receptor. (1S,2S)-Cyclopropylhistamine (VUF 5297) acts as an agonist both on the rat cortex (pD2 = 7.1; alpha = 0.75) and on guinea pig jejunum (pD2 = 6.6; alpha = 0.75). Its enantiomer, (1R, 2R)-cyclopropylhistamine (VUF 5296), is about 1 order of magnitude less active. Both enantiomers show weak activity on H1 and H2 receptors. All synthetic attempts to cis-cyclopropylhistamine were unsuccessful. Nevertheless, the results of this study provide an ideal template for molecular modeling studies of histamine H3 receptor ligands.

Animals↗
PubMed1999

Non-imidazole histamine H3 ligands, Part 2: New 2-substituted benzothiazoles as histamine H3 antagonists.

New, non-imidazole histamine H3 receptor antagonists were prepared and in vitro tested as H3 receptor antagonists measured as the electrically evoked contraction of the guinea-pig jejunum. The 2-(1-piperidinyl)- and 2-(1-pyrrolidinyl)benzothiazoles show no or very poor activity; 2-[1-(4-amino)piperidinyl]- and 2-(1,2-ethanediamino)- and 2-(1,3-propanediamino)derivatives of benzothiazole possess weak activity at H3 receptors, whereas 2-(4-piperidinyl)benzothiazoles and 2-[1-(4-piperazinyl)]benzothiazoles show moderate to good activity. Lipophilic and not-too-bulky substituents like n-propyl attached to the nitrogen at the piperazine or piperidine ring lead to potent H3 receptor antagonists with pA2 values ranging from 7.0 to 7.2. The structure-activity relationships for different substitution patterns are discussed.

Animals↗