Compared pharmacology of human histamine H₃ and H₄ receptors: structure–activity relationships of histamine derivatives

Abstract

4 Histamine derivatives substituted with methyl groups in a, b or N a 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, (7)-a,bdimethylhistamine is a potent and selective H 3 R agonist. 5 Chiral a-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. 6 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 ¼ 7.071.2 nM) and very low potency at H 1 -and H 3 -receptors, it can be considered as a potent and selective H 4 R 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 4 R (BÀ30%) was much lower than at the H 3 R (BÀ80%). Thioperamide behaved as an inverse agonist at both receptors and increased cAMP formation with the same maximal effect (B þ 25%). 8 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.

Histamine H3 Receptor Antagonists Go to Clinics

“…[51][52][53] Studies comparing the receptor pharmacology of hH 3 R and hH 4 R show remarkable differences in SAR of imidazole-containing ligands concerning affinity and efficacy 49,54) (Figs. 3, 4).…”

“…50) The hH 4 R possesses a higher similarity to hH 3 R with a sequence homology ranging from 38% up to 58% within the transmembrane domains. [51][52][53] Studies comparing the receptor pharmacology of hH 3 R and hH 4 R show remarkable differences in SAR of imidazole-containing ligands concerning affinity and efficacy 49,54) (Figs. 3, 4).…”

Chemokine Secretion Patterns in Mononuclear and Dendritic Cells: Role of Histamine Type H3/H4 Receptors

“…Различная экспрессия и эффекторная функ-ция участков и структур этого сигнального пути зависит от стадии созревания/дифференциров-ки, тканевой принадлежности и активности кле-ток-мишеней, на основании чего развиваются многообразные реакции в биологических систе-мах [2,4,12,18,21,23]. В настоящее время нако-плено значительное количество данных, свиде-тельствующих об экспрессии на поверхности мононуклеаров периферической крови (МПК) и дендритных клеток (ДК) всех 4-х известных ти-пов Н-рецепторов [3,7,8,9,10,11,13,22,23].…”

From Receptors to Ligands: Fragment-assisted Drug Design for GPCRs Applied to the Discovery of H3 and H4 Receptor Antagonists

“…This is due to the current infeasibility of regularly crystallizing the GPCR-fragment complexes that are required for further fragment expansion. Recently, there has been several lines of evidence suggesting that FADD might be useful for GPCR hit identification [5]. These publications encouraged us to try this approach in the discovery of GPCR antagonists.…”

“…The histamine GPCRs signal through Gi/o proteins leading to inhibition of cAMP formation, mobilisation of calcium from intracellular stores and stimulation of MAP kinase in both heterologous expression systems and native immune cells [5,6]. H3 and H4 receptors remain highly attractive targets for drug discovery and medicinal chemistry development programs [7][8][9][10].…”