Development of Novel Chiral Cyclic Histamine H3 Agonists

The long-term objectives are to synthesize novel cyclic and heterocyclic histamine H3 receptor agonprodrugs thereof that have improved GI absorption and CNS penetration. These agents are being develotreatment of acute and chronic insomnia. The Specific Aims of this grant are (1) to synthesize varioheterocyclic H3 receptor agonists and azomethine prodrugs thereof; (2) to test for receptor affinitybinding assay using [3H]-N-alpha-methylhistamine and to determine receptor selectivity for the H3 reand H2 receptors using standard receptor binding assays; (3) to characterize the in vivo H3 receptorpenetration profiles of novel H3 agonists and prodrugs using ex vivo binding procedures; (4) to funcvivo histamine release of selected novel agonists by measuring Histamine/Nt-methylhistamine (TMH) lethus indirectly assessing autoreceptor activation; (5) and finally, quantifying the potential sedatiagonists by utilizing the pentobarbital-induced righting reflex paradigm. This research would possibtreatments for sleep disorders including excess insomnolence.