Mechanistic characterization of S 38093, a novel inverse agonist at histamine H3 receptors

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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 1.2 μM, respectively) with no affinity for other histaminergic receptors.

In cellular models, the compound was able to antagonize mice H3 receptors (KB=0.65 μM) and to suppress cAMP decrease induced by an H3 agonist via human H3 receptors (KB=0.11 μM). The antagonism properties of the compound were confirmed by electrophysiological studies on rat hippocampal slices (from 0.1 μM). In cells expressing a high H3 density, S 38093 behaved as a moderate inverse agonist at rat and human H3 receptors (EC50=9 and 1.7 μM, respectively).

S 38093 was rapidly absorbed in mouse and rat (Tmax=0.25–0.5 h), slowly in monkey (2 h), with a bioavailability ranging from 20% to 60% and t1/2 ranging from 1.5 to 7.4 h. 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 3 mg/kg p.o. and antagonized R-α-Methylhistamine-induced dipsogenia from 10 mg/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.

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