Compared pharmacology of human histamine H 3 and H 4 receptors: Structure-activity relationships of histamine derivatives

Abstract

1 Various histamine derivatives were investigated at the human H 3 receptor (H 3R) and H 4 receptor (H 4R) stably expressed in human embryonic kidney (HEK)-293 cells using [ 125I]iodoproxyfan and [ 3H]histamine binding, respectively. 2 In Tris buffer, [ 3H]histamine binding to membranes of HEK(hH 4R) 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). 3 The inhibition of [ 3H]histamine binding by two agonists, a protean agonist and five antagonists/ inverse agonists confirms that the potency of many H 3R ligands is retained or only slightly reduced at the H 4R. 4 Histamine derivatives substituted with methyl groups in α, β or N α position of the side chain retained a nanomolar potency at the H 3R, but their affinity was dramatically decreased at the H 4R. With relative potencies to histamine of 282 and 0.13% at the H 3R and H 4R, respectively, (±)-α,β- dimethylhistamine is a potent and selective H 3R agonist. 5 Chiral α-branched analogues exhibited a marked stereoselectivity at the H 3R and H 4R, the enantiomers with a configuration equivalent to L-histidine being preferred at both receptors. 6 The methylsubstitution of the imidazole ring was also studied. The relative potency to histamine of 4-methylhistamine (4-MeHA) at the H 4R (67%) was similar to that reported at H 2 receptors but, owing to its high affinity at the H 4R (K i = 7.0 ± 1.2 nM) and very low potency at H 1- and H 3-receptors, it can be considered as a potent and selective H 4R agonist. 7 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 4R (∼-30%) was much lower than at the H 3R (∼-80%). Thioperamide behaved as an inverse agonist at both receptors and increased cAMP formation with the same maximal effect (∼+25%). 8 In conclusion, although the pharmacological profiles of the human H 3R and H 4R overlap, the structure-activity relationships of histamine derivatives at both receptors strongly differ and lead to the identification of selective compounds. © 2006 Nature Publishing Group All rights reserved.