Abstract：
: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 t1/2 ranging 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.
journal_name
Eur J Pharmacoljournal_title
European journal of pharmacologyauthors
Sors A,Panayi F,Bert L,Favale D,Nosjean O,Audinot V,Arrang JM,Buisson B,Steidl E,Delbos JM,Huhtala T,Kontkanen O,Chollet AM,Casara P,Lestage Pdoi
10.1016/j.ejphar.2017.03.013subject
Has Abstractpub_date
2017-05-15 00:00:00pages
11-23eissn
0014-2999issn
1879-0712pii
S0014-2999(17)30160-7journal_volume
803pub_type
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