S 38093 Histamine Receptor antagonist

In cellular models, this compound was able to antagonise 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). Among the four histaminergic receptor subtypes, it is selective for the H3 receptor, its binding affinity for H1, H2 and H4 receptors being negligible[1].

S 38093, a novel brain-penetrant antagonist/inverse agonist of H3 receptors, on AHN (proliferation, maturation and survival) in 3-month-old and in aged 16-month-old mice. In aged animals, this compound induced a reversal of age-dependent effects on hippocampal brain-derived neurotrophic factor (BDNF) BDNF-IX, BDNF-IV and BDNF-I transcripts and increased vascular endothelial growth factor (VEGF) expression. The effects of chronic administration of this compound were assessed on a neurogenesis-dependent “context discrimination (CS) test” in aged mice. While ageing altered mouse CS, chronic treatment with this chemical significantly improved CS. Chronic treatment with this compound increases adult hippocampal neurogenesis and may provide an innovative strategy to improve age-associated cognitive deficits. This compound is found to be active at a mean pharmacological dose of 0.3–1 mg/kg p.o./i.p. in animal behavioural tests of working memory (Morris water maze in rats; spontaneous alternation and concurrent serial alternation tests in mice; delayed matching to sample in aged monkeys) and episodic-like memory (social and object recognition tests in rats; contextual discrimination task in mice). It also improves attention, executive functioning, and cognitive flexibility in MPTP-treated monkeys. Moreover, in line with its H3 antagonist/inverse agonist properties, this chemical dose-dependently increases extracellular histamine levels in the prefrontal cortex and facilitates cholinergic transmission in the prefrontal cortex and hippocampus of rats after both acute and chronic administrations[2]. This compound 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 1.5h to 7.4h. The compound was widely distributed with a moderate volume of distribution and low protein binding. The brain distribution of this chemical was rapid and high[1].