Leschke C, Elz S, Garbarg M, Schunack W
Institute of Pharmacy, Freie Universität Berlin, Germany.
J Med Chem. 1995 Apr 14;38(8):1287-94. doi: 10.1021/jm00008a007.
New histamine derivatives characterized by a (substituted) aryl, heteroaryl, benzyl, or heteroarylmethyl substituent in the C2 position of the imidazole ring have been prepared from appropriate imidates or amidines, respectively, and 2-oxo-4-phthalimido-1-butyl acetate (1). The compounds were screened as potential H1 receptor agonists on the isolated guinea pig ileum. The 3-halogenated 2-phenylhistamines (halogen = Br (35) and I (36)) were equipotent with histamine, while 2-(3-(trifluoromethyl)phenyl)histamine (2-[2-(3-(trifluoromethyl)phenyl)-1H-imidazol-4-yl]ethanamine (39)) was significantly more potent than histamine (39: pD2 = 6.81, relative activity = 128%). The 2-substituted histamine analogues were partial H1 receptor agonists on the endothelium-denuded isolated guinea pig aorta with pEC50 values generally smaller than observed on the guinea pig ileum, but the rank order of potency was found to be similar. The contractile effects on guinea pig ileum and aorta, respectively, could be blocked concentration-dependently by the H1 receptor antagonist mepyramine, yielding KB values for mepyramine in the nanomolar range. In vitro compounds 35 and 39 bound to [3H]mepyramine-labeled guinea pig cerebellar membranes with a pKi of 6.1 and 5.9, respectively. However, upon iv administration, 35 (3-100 mg/kg) and 39 (3-300 mg/kg) failed to inhibit the binding of [3H]mepyramine to mouse cerebral cortex in vivo, thereby indicating that these histamine derivatives are not able to penetrate the blood-brain barrier. In functional in vitro studies on histamine H2, H3, and other neurotransmitter receptors the selectivity of 39 was found to be 2138 (H1:H2), > 64 (H1:H3), 1000 (H1:M3), 105 (H1:alpha 1), 708 (H1:beta 1), and 71 (H1:5HT2A). Thus compound 39 is the most potent and selective H1 receptor agonist reported so far. These results make meta-substituted 2-phenylhistamines, especially 2-(3-(trifluoromethyl)phenyl)- and 2-(3-bromophenyl)histamine (39 and 35, respectively) valuable experimental tools for the selective stimulation of histamine H1 receptors and the study of H1 receptor-mediated functions.
新型组胺衍生物已分别由合适的亚氨酸酯或脒与2-氧代-4-邻苯二甲酰亚胺基-1-丁基乙酸酯（1）制备而成，其特征在于咪唑环C2位上有一个（取代的）芳基、杂芳基、苄基或杂芳基甲基取代基。这些化合物在离体豚鼠回肠上作为潜在的H1受体激动剂进行了筛选。3-卤代-2-苯基组胺（卤素 = Br（35）和I（36））与组胺效力相当，而2-(3-(三氟甲基)phenyl)组胺（2-[2-(3-(三氟甲基)phenyl)-1H-咪唑-4-基]乙胺（39））的效力明显高于组胺（39：pD2 = 6.81，相对活性 = 128%）。2-取代组胺类似物在去内皮的离体豚鼠主动脉上是部分H1受体激动剂，其pEC50值通常小于在豚鼠回肠上观察到的值，但效力顺序相似。对豚鼠回肠和主动脉的收缩作用分别可被H1受体拮抗剂美吡拉敏浓度依赖性地阻断，美吡拉敏的KB值在纳摩尔范围内。体外实验中，化合物35和39与[3H]美吡拉敏标记的豚鼠小脑膜结合，pKi分别为6.1和5.9。然而，静脉给药时，35（3 - 100 mg/kg）和39（3 - 300 mg/kg）在体内未能抑制[3H]美吡拉敏与小鼠大脑皮层的结合，从而表明这些组胺衍生物无法穿透血脑屏障。在对组胺H2、H3和其他神经递质受体的体外功能研究中，发现39的选择性为2138（H1:H2）、> 64（H1:H3）、1000（H1:M3）、105（H1:α1）、708（H1:β1）和71（H1:5HT2A）。因此，化合物39是迄今为止报道的最有效和选择性最高的H1受体激动剂。这些结果使得间位取代的2-苯基组胺，尤其是2-(3-(三氟甲基)phenyl)-和2-(3-溴phenyl)组胺（分别为39和35）成为选择性刺激组胺H1受体和研究H1受体介导功能的有价值的实验工具。
