ACYLATED AND ALKYLATED HISTAMINE DERIVATIVES AS NEW HISTAMINE H-3 RECEPTOR ANTAGONISTS

New histamine H-3-receptor antagonists were prepared and investigated for their ability to increase synthesis and release of histamine media ted by inhibition of presynaptically located H-3-receptors. Acyl deriv atives of histamine methylated at different positions show poor activi ty at H-3-receptors, whereas N-alpha-alkyl and particularly N-alpha-ac yl derivatives of histamine possess moderate to good H-3-receptor anta gonist activity. A not-too-bulky and lipophilic residue in an optimal distance of 3-4 methylene groups from the amide function leads to pote nt and selective H-3-receptor antagonists. N-alpha-Histamine-gamma-phe nylbutyramide 11 and N-alpha-histamine-gamma-cyclohexylbutyramide 13 a re H-3-receptor antagonists with -log K-i of 7.1 and 7.3, respectively . Structure-activity relationships of different substitution patterns are discussed.