Acylated and alkylated histamine derivatives as new histamine H3-receptor antagonists

Article abstract of DOI:10.1016/0223-5234(94)90031-0

New histamine H3-receptor antagonists were prepared and investigated for their ability to increase synthesis and release of histamine mediated by inhibition of presynaptically located H3-receptors.Acyl derivatives of histamine methylated at different positions show poor activity at H3-receptors, whereas N^α-alkyl and particularly N^α-acyl derivatives of histamine possess moderate to good H3-receptor antagonist activity.A not-too-bulky and lipophilic residue in an optimal distance of 3-4 methylene groups from the amide function leads to potent and selective H3-receptor antagonists.N^α-Histamine-γ-phenylbutyramide 11 and N^α-histamine-γ-cyclohexylbutyramide 13 are H3-receptor antagonists with -log K_i of 7.1 and 7.3, respectively.Structure-activity relationships of different substitution patterns are discussed. histamine / histamine H3-receptor antagonist / N^α-alkylated histamine / N^α-acylated histamine / N^α-histamine-γ-cyclohexylbutyramide