Stark H, Ligneau X, Lipp R, Arrang J M, Schwartz J C, Schunack W
Institut für Pharmazie I, Freie Universität Berlin, Germany.
Pharmazie. 1997 Jun;52(6):419-23.
In search for novel leads for histamine H3-receptor antagonists a number of amine derivatives of different (1 H-imidazol-4-yl)anilines and omega-(1 H-imidazol-4-yl)alkanamines were prepared. Pharmacological in vitro H3-receptor investigations of the prepared urea, amide, inverse amide, thioamide, and thiourea derivatives on synaptosomes of rat cerebral cortex proved that the aniline derivatives are inactive at H3-receptors, whereas derivatives of the omega-(1 H-imidazol-4-yl)-alkanamines showed moderate to good activity. Some compounds are active in the nanomolar concentration range. The most potent compounds in this series are the thioamide derivative 7 and the urea derivatives 11, 12 of 3-(1 H-imidazol-4-yl) propanamine. Therefore, the urea derivatives were tested in vitro on isolated organs of the guinea pig for their activity on the other two histamine receptor subtypes proving their high selectivity. In vivo studies of the effects of the urea derivatives 11 and 12 on brain Nt-methylhistamine levels, a test of central H3-receptor activity after peroral application to mice, showed no detectable activity. Thus, the urea type antagonists are useful potent and selective H3-receptor tools for in vitro studies and for investigations of ligand-receptor interactions.
为了寻找组胺H3受体拮抗剂的新型先导化合物，制备了多种不同的（1H-咪唑-4-基）苯胺和ω-（1H-咪唑-4-基）链烷胺的胺衍生物。对所制备的脲、酰胺、反式酰胺、硫代酰胺和硫脲衍生物在大鼠大脑皮层突触体上进行的体外H3受体药理学研究证明，苯胺衍生物在H3受体上无活性，而ω-（1H-咪唑-4-基）链烷胺的衍生物表现出中等至良好的活性。一些化合物在纳摩尔浓度范围内具有活性。该系列中最有效的化合物是硫代酰胺衍生物7以及3-（1H-咪唑-4-基）丙胺的脲衍生物11、12。因此，对脲衍生物在豚鼠离体器官上进行了体外测试，以检测它们对其他两种组胺受体亚型的活性，结果证明它们具有高选择性。对脲衍生物11和12经口给予小鼠后对脑Nt-甲基组胺水平的影响进行的体内研究，这是一种中枢H3受体活性测试，结果显示未检测到活性。因此，脲型拮抗剂是用于体外研究和配体-受体相互作用研究的有效且选择性的H3受体工具。
