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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Vincent, Ludwig Humbert-claude, Marie Gbahou, Florence Arrang, Jean-michel Tardivel-lacombe, Joel Chabret, Claude |
| Description | Author Affiliation: Gbahou F ( INSERM, Unité de Neurobiologie et Pharmacologie Moléculaire (U573), Centre Paul Broca, 2 ter rue d'Alésia, 75014 Paris, France.) |
| Abstract | Various histamine derivatives were investigated at the human H3 receptor (H3R) and H4 receptor (H4R) stably expressed in human embryonic kidney (HEK)-293 cells using [125I]iodoproxyfan and [3H]histamine binding, respectively. In Tris buffer, [3H]histamine binding to membranes of HEK(hH4R) cells was monophasic (K(D) of 3.8+/-0.8 nM). In phosphate buffer, the Hill coefficient was decreased (n(H) = 0.5+/-0.1) and a large fraction of the binding was converted into a low-affinity component (K(D) = 67+/-27 nM). The inhibition of [3H]histamine binding by two agonists, a protean agonist and five antagonists/inverse agonists confirms that the potency of many H3R ligands is retained or only slightly reduced at the H4R. Histamine derivatives substituted with methyl groups in alpha, beta or N(alpha) position of the side chain retained a nanomolar potency at the H3R, but their affinity was dramatically decreased at the H4R. With relative potencies to histamine of 282 and 0.13% at the H3R and H4R, respectively, (+/-)-alpha,beta-dimethylhistamine is a potent and selective H3R agonist. Chiral alpha-branched analogues exhibited a marked stereoselectivity at the H3R and H4R, the enantiomers with a configuration equivalent to L-histidine being preferred at both receptors. The methylsubstitution of the imidazole ring was also studied. The relative potency to histamine of 4-methylhistamine (4-MeHA) at the H4R (67%) was similar to that reported at H2 receptors but, owing to its high affinity at the H4R (Ki = 7.0+/-1.2 nM) and very low potency at H1- and H3-receptors, it can be considered as a potent and selective H4R agonist. On inhibition of forskolin-induced cAMP formation, all the compounds tested, including 4-MeHA, behaved as full agonists at both receptors. However, the maximal inhibition achieved at the H4R (approximately -30%) was much lower than at the H3R (approximately -80%). Thioperamide behaved as an inverse agonist at both receptors and increased cAMP formation with the same maximal effect (approximately +25%). In conclusion, although the pharmacological profiles of the human H3R and H4R overlap, the structure-activity relationships of histamine derivatives at both receptors strongly differ and lead to the identification of selective compounds. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 7 |
| Volume Number | 147 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 2006-04-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Histamine Analogs & Derivatives Pharmacology Receptors, G-Protein-Coupled Drug Effects Receptors, Histamine H3 Receptors, Histamine Binding, Competitive Colforsin Cyclic AMP Metabolism DNA, Complementary Biosynthesis Genetics Histamine H2 Antagonists Imidazoles In Vitro Techniques Kidney Cytology Recombinant Proteins Structure-Activity Relationship Transfection Comparative Study |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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