S-[2-(4-imidazolyl)ethyl]isothiourea, a highly specific and potent histamine H3 receptor agonist.
The effects of a new agonist of histamine (HA) H3 receptors, Imetit (S-[2-(4-(imidazolyl)ethyl]isothiourea) were investigated in vitro and in vivo and compared to those of (R)-alpha-methylhistamine [(R)-alpha-MeHA], a prototypic drug. Imetit inhibited the binding of [3H](R-alpha-MeHA to rat brain membranes with a Ki value of 0.1 +/- 0.01 nM. The release of endogenously synthesized [3H]HA induced by K(+)-depolarization from rat brain slices and synaptosomes was inhibited by Imetit with EC50 values of 1.0 +/- 0.3 and 2.8 +/- 0.7 nM, respectively. Imetit behaved as a full agonist and was about 4 times more potent than (R)-alpha-MeHA and 60 times more potent than HA. Thioperamide, a selective H3 receptor antagonist, elicited a parallel rightward shift of the concentration-response curve for Imetit with an apparent Ki value of 5.6 +/- 1.4 nM. Imetit potencies relative to HA were less than 0.1% and only 0.6% at HA H1 and H2 receptor reference systems, respectively. Imetit was found not to be a substrate or an inhibitor of HMT. After p.o. administration to mice or rats, Imetit decreased (by approximately 50%) the tele-MeHA level in the cerebral cortex with ED50 values of 1.0 +/- 0.3 and 1.6 +/- 0.3 mg/kg, respectively. This effect was still maximal after 6 hr. The in vivo potency and duration of action of Imetit were in the same range as those of (R)-alpha-MeHA. It is therefore concluded that Imetit represents a new potent and selective HA H3 receptor agonist.
Garbarg
M
M
Unité de Neurobiologie et Pharmacologie (U. 109), Institut National de la Santé et de la Recherche Médicale, Centre Paul Broca, Paris, France.
Arrang
J M
JM
Rouleau
A
A
Ligneau
X
X
Tuong
M D
MD
Schwartz
J C
JC
Ganellin
C R
CR
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006168:Guinea Pigs; D017442:Histamine Agonists / Q000494:pharmacology*; D006637:Histamine N-Methyltransferase / Q000378:metabolism; D006636:Histamine Release / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D008761:Methylhistamines / Q000378:metabolism; D051379:Mice; D051381:Rats; D011968:Receptors, Histamine / Q000187:drug effects*; D018100:Receptors, Histamine H3; D013890:Thiourea / Q000031:analogs & derivatives; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
D017442:Histamine Agonists; D007093:Imidazoles; D008761:Methylhistamines; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; C077430:imetit; D014508:Urea; D006637:Histamine N-Methyltransferase; D013890:Thiourea