Compared pharmacology of human histamine H 3 and H 4 receptors: structure–activity relationships of histamine derivatives

• Published in: British journal of pharmacology 2006-04, Vol.147 (7), p.744-754
• Main Authors: Gbahou, Florence, Vincent, Ludwig, Humbert‐Claude, Marie, Tardivel‐Lacombe, Joel, Chabret, Claude, Arrang, Jean‐Michel
• Format: Article
• Language: English
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0706666

Various histamine derivatives were investigated at the human H 3 receptor (H 3 R) and H 4 receptor (H 4 R) stably expressed in human embryonic kidney (HEK)‐293 cells using [ 125 I]iodoproxyfan and [ 3 H]histamine binding, respectively. In Tris buffer, [ 3 H]histamine binding to membranes of HEK(hH 4 R) cells was monophasic ( K D of 3.8±0.8 n M ). 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 n M ). The inhibition of [ 3 H]histamine binding by two agonists, a protean agonist and five antagonists/inverse agonists confirms that the potency of many H 3 R ligands is retained or only slightly reduced at the H 4 R. Histamine derivatives substituted with methyl groups in α , β or N α position of the side chain retained a nanomolar potency at the H 3 R, but their affinity was dramatically decreased at the H 4 R. With relative potencies to histamine of 282 and 0.13% at the H 3 R and H 4 R, respectively, (±)‐ α , β ‐dimethylhistamine is a potent and selective H 3 R agonist. Chiral α ‐branched analogues exhibited a marked stereoselectivity at the H 3 R and H 4 R, 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 H 4 R (67%) was similar to that reported at H 2 receptors but, owing to its high affinity at the H 4 R ( K i =7.0±1.2 n M ) and very low potency at H 1 ‐ and H 3 ‐receptors, it can be considered as a potent and selective H 4 R 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 H 4 R (∼−30%) was much lower than at the H 3 R (∼−80%). Thioperamide behaved as an inverse agonist at both receptors and increased cAMP formation with the same maximal effect (∼+25%). In conclusion, although the pharmacological profiles of the human H 3 R and H 4 R overlap, the structure–activity relationships of histamine derivatives at both receptors strongly differ and lead to the identification of selective compounds. British Journal of Pharmacology (2006) 147 , 744–754. doi: 10.1038/sj.bjp.0706666