Mechanistic characterization of S 38093, a novel inverse agonist at histamine H3 receptors.
Histaminergic H3 inverse agonists, by stimulating central histamine release, represent attractive drug candidates to treat cognitive disorders. The present studies aimed to describe the mechanistic profile of S 38093 a novel H3 receptors inverse agonist. S 38093 displays a moderate affinity for rat, mouse and human H3 receptors (Ki=8.8, 1.44 and 1.2µM, respectively) with no affinity for other histaminergic receptors. In cellular models, the compound was able to antagonize mice H3 receptors (KB=0.65µM) and to suppress cAMP decrease induced by an H3 agonist via human H3 receptors (KB=0.11µM). The antagonism properties of the compound were confirmed by electrophysiological studies on rat hippocampal slices (from 0.1μM). In cells expressing a high H3 density, S 38093 behaved as a moderate inverse agonist at rat and human H3 receptors (EC50=9 and 1.7µM, respectively). S 38093 was rapidly absorbed in mouse and rat (Tmax=0.25-0.5h), slowly in monkey (2h), with a bioavailability ranging from 20% to 60% and t1/2ranging from 1.5 to 7.4h. The compound was widely distributed with a moderate volume of distribution and low protein binding. The brain distribution of S 38093 was rapid and high. In mice, S 38093 significantly increased ex vivo N-tele-Methylhistamine cerebral levels from 3mg/kg p.o. and antagonized R-α-Methylhistamine-induced dipsogenia from 10mg/kg i.p. Taken together, these data suggest that S 38093, a novel H3 inverse agonist, is a good candidate for further in vivo evaluations, in particular in animal models of cognition.
Pôle d'Innovation Thérapeutique Neuropsychiatrie Servier, Croissy-sur-Seine et Suresnes, France. Electronic address: aurore.sors@servier.com.
Aurore
A
Sors
Pôle d'Innovation Thérapeutique Neuropsychiatrie Servier, Croissy-sur-Seine et Suresnes, France.
Fany
F
Panayi
Pôle d'Innovation Thérapeutique Neuropsychiatrie Servier, Croissy-sur-Seine et Suresnes, France.
Lionel
L
Bert
Pôle d'Innovation Thérapeutique Neuropsychiatrie Servier, Croissy-sur-Seine et Suresnes, France.
Dominique
D
Favale
Pôle d'Expertise Recherche et Biopharmacie, Servier, Croissy-sur-Seine et Orléans, France.
Olivier
O
Nosjean
Pôle d'Expertise Recherche et Biopharmacie, Servier, Croissy-sur-Seine et Orléans, France.
Valérie
V
Audinot
INSERM U 894, Paris, France.
Jean-Michel
JM
Arrang
Neuroservice, Aix-en-Provence, France.
Bruno
B
Buisson
Neuroservice, Aix-en-Provence, France.
Esther
E
Steidl
Pôle d'Expertise Recherche et Biopharmacie, Servier, Croissy-sur-Seine et Orléans, France.
Jean-Marie
JM
Delbos
Charles River Discovery Research Services, Kuopio, Finland.
Tuulia
T
Huhtala
Charles River Discovery Research Services, Kuopio, Finland.
Outi
O
Kontkanen
Pôle d'Expertise Recherche et Biopharmacie, Servier, Croissy-sur-Seine et Orléans, France.
Anne-Marie
AM
Chollet
Pôle d'Expertise Recherche et Biopharmacie, Servier, Croissy-sur-Seine et Orléans, France.
Patrick
P
Casara
Pôle d'Innovation Thérapeutique Neuropsychiatrie Servier, Croissy-sur-Seine et Suresnes, France.
Pierre
P
Lestage
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006632:Histamine / Q000378:metabolism; D017442:Histamine Agonists / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D054828:Histamine H3 Antagonists / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D051381:Rats; D018100:Receptors, Histamine H3 / Q000378:metabolism*
D053961:Azabicyclo Compounds; D001549:Benzamides; D017442:Histamine Agonists; D054828:Histamine H3 Antagonists; D018100:Receptors, Histamine H3; C000624696:S 38093; D016718:Arachidonic Acid; D006632:Histamine; D000242:Cyclic AMP
Antagonist; Electrophysiology; Functionality; H3; Inverse agonist; Pharmacokinetics