Synthesis and histamine H3-receptor agonist activity of mono- and dialkyl-substituted histamine derivatives

Article abstract of DOI:10.1016/0223-5234(96)88228-6

In search for potential histamine H₃-receptor agonists a series of mono- and dialkyl-substituted histamine derivatives was synthesized.All target compounds were tested in vitro for their agonist activity at H₃-, H₂, and H₁-receptors.Introduction of one ethyl or two methyl residues into histamine led to compounds with decreased histamine H₃-agonist potency in most cases.However, the non-chiral α,α-dimethylhistamine (15) was identified to be three times as active as histamine itself at H₃-receptors.In addition 15 shows high receptor selectivity being20000 times as active at H₃- as at H₂- and H₁-receptors, respectively. (αR)-αN^τ-Dimethylhistamine 23, which is a potential metabolite of (αR)-α-methylhistamine 1, proved to be inactive at all three histamine receptor subtypes. α,α-dimethylhistamine / (αR)-αN^τ-dimethylhistamine / histamine H³-receptor / agonist