Development of selective ligands to histamine H3 and H4 receptors and its application to elucidate the physiological function of the receptors.

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Histamine H4-receptor is the most recently discovered histamine receptor which has 35% overall homology to the H3-receptor. However, the tissue distribution of the two receptors is quite different. To elucidate the physiological and pathophysiological functions of the receptors, development of selective ligands to both receptors is indispensable. In this study, we synthesized a series of tetrahydrofuranylimidazole and tetrahydropyranylimidazole derivatives and examined the binding and functional activities on the receptors. Among them, we found two tetrahydrofuranylimidazoles as selective H4-agonists, OUP-13 and OUP-16, and two tetrahydropyranylimidazoles as selective H3-antagonists, OUP-152 and OUP-153.The H4-agonists inhibited histamine release form RBL-2H3 cells induced by low concentration of DNP-BSA antigen, indicating H4-receptor may regulate the allergic histamine release.In addition, we examined physiological function of the brain histaminergic system and found that central histamine participate in the transmission of taste information. Furthermore, we also found that a target of modafinil, a novel drug for narcolepsy, is the histaminergic system. This finding indicates that H3-antagonists may useful to treat narcolepsy.