[Potential interest in powerful and specific ligands for the histamine H3 receptor]

In contrast to cerebral histamine H1 and H2-receptors, histamine H3-receptors are presynaptically located on histamine-synthesizing nerve terminals (autoreceptors) and control the synthesis and release of the amine in cerebral neurons. Two imidazole derivatives were designed to interact at H3-receptors: (R) alpha-methylhistamine (alpha-MeHA), a chiral agonist, and thioperamide, a competitive antagonist derived from imidazolyl piperidine, both display high selectivity and potency at nanomolar concentrations in vitro. (R) alpha-MeHA, being about 15 times as potent as histamine itself, constitutes, when tritiated, a suitable probe for the radioassay of H3-receptors. Outside the brain, H3-receptor sites could be detected in the lung. The availability of new ligands made it possible to assess in vivo the physiological role of central and peripheral H3-receptors. The agonist and the antagonist modified in opposite directions histamine synthesis in the lung as in the brain, confirming the presence of H3-receptors in this peripheral organ. A large part of lung histamine being present within mast-cells, it is likely that these cells are endowed with H3-receptors controlling the amine synthesis and, possibly, release. Therefore, the novel agents may be of great practical interest in the field of allergy and inflammation.