Histamine is an important neurotransmitter exerting its actions via four classes of molecularly and/or pharmacologically well-defined receptors. They differ in distribution, pharmacology, and function. The H3 receptor is a member of the large superfamily of G protein-coupled receptors. It has mostly pre-synaptic localization and its activation leads to the inhibition of the synthesis and release of histamine. Likely, presynaptic H3 receptors on heterologous nerve endings negatively regulate the release of neurotransmitters such as acetylcholine, serotonin, noradrenaline, and dopamine. Adult neurogenesis occurs in the subgranular zone of the hippocampal dentate gyrus of adult mammalian brains. S 38093 promotes hippocampal neurogenesis and improves context discrimination tasks in aged mice. Besides, it is a brain-penetrant antagonist of the H3 receptor.
S 38093 is a brain-penetrant antagonist of the H3 receptor.
S 38093 shows the Kis of 8.8, 1.44, and 1.2 µM for rat, mouse, and human H3 receptors, respectively. In cellular models, it can antagonize mice H3 receptors (KB=0.65 µM). Moreover, it suppresses the cAMP decrease induced by an H3 agonist via human H3 receptors (KB=0.11 µM). In cells expressing a high H3 density, S 38093 also behaves like a moderate inverse agonist at the rat and human H3 receptors (EC50=9 and 1.7 µM, respectively). Besides, S 38093 significantly increases the proliferation of progenitors in the dentate gyrus (DG) of the hippocampus in young adult mice. Furthermore, S 38093 treatment significantly increases the number of DCX+ cells with tertiary dendrites. In a word, S 38093 significantly increases cell proliferation, survival, and maturation in the DG of the hippocampus in aged mice.
In summary, S 38093 is a novel H3 inverse agonist. It is a good candidate for further in vivo evaluations, in particular in animal models of cognition.