[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.
Arrang
J M
JM
Unité 109 de Neurobiologie et Pharmacologie, Centre Paul Broca de l'INSERM, Paris, France.
Garbarg
M
M
Lancelot
J C
JC
Lecomte
J M
JM
Pollard
H
H
Robba
M
M
Schunack
W
W
Schwartz
J C
JC
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects; D006168:Guinea Pigs; D006632:Histamine / Q000096:biosynthesis; D006636:Histamine Release / Q000187:drug effects; D066298:In Vitro Techniques; D008024:Ligands; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008761:Methylhistamines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D011968:Receptors, Histamine / Q000145:classification / Q000187:drug effects*
D008024:Ligands; D008761:Methylhistamines; D010880:Piperidines; D011968:Receptors, Histamine; D006632:Histamine; C052075:thioperamide
Intérêt potentiel de ligands puissants et spécifiques du récepteur H3 de l'histamine.