[CAS NO. 862896-30-8]  S 38093

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, S 38093 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 S 38093 were assessed on a neurogenesis-dependent “context discrimination (CS) test” in aged mice. While ageing altered mouse CS, chronic S 38093 treatment significantly improved CS. Chronic S 38093 treatment increases adult hippocampal neurogenesis and may provide an innovative strategy to improve age-associated cognitive deficits. S 38093 is found to be active at a mean pharmacological dose of 0.3–1 mg/kg p.o./i.p. in animal behavioral 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). S 38093 also improves attention, executive functioning, and cognitive flexibility in MPTP-treated monkeys. Moreover, in line with its H3 antagonist/inverse agonist properties, S 38093 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. 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 1.5h 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.