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

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Abstract

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 Nα-alkyl and particularly Nα-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. Nα-Histamine-γ-phenylbutyramide II and Nα-histamine-γ-cyclohexylbutyramide 13 are H3-receptor antagonists with — log Ki of 7.1 and 7.3, respectively. Structure-activity relationships of different substitution patterns are discussed.

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