Institut für Pharmazie, Lehrstuhl für Pharmazeutische/Medizinische Chemie, Friedrich Schiller Universität Jena, Philosophenweg 14, D-07743 Jena.
Chem Biodivers. 2011 Mar;8(3):431-9. doi: 10.1002/cbdv.201000317.
Dibenzazecines are a novel class of dopamine receptor antagonists, characterized by their high affinities as well as their tendency for D(1) selectivity. Hitherto, the most active dibenzazecines were phenolic in nature; a 3-OH substituent was found to result in the highest affinities. However, the phenolic nature of these compounds mostly renders them unsuitable for in vivo application, due to the poor pharmacokinetic profile, imparted by the phenolic group. A novel dibenzazecine derivative was prepared, with methylenedioxy moiety, connecting C(2) amd C(3), instead of the 3-OH group. The newly synthesized derivative 3 showed high affinities similar to the lead LE404, displaying nanomolar affinities for all dopamine receptor subtypes. Its dibrominated derivative 4, though exhibiting almost a fivefold decrease in affinities, still displayed nanomolar ones for all dopamine receptors, except for D(4) . In a functional Ca(2+) assay, both compounds 3 and 4 were found to possess antagonistic properties towards the dopamine receptors.
二苯并氮杂卓类是一类新型的多巴胺受体拮抗剂，具有高亲和力和 D1 选择性。迄今为止，最有效的二苯并氮杂卓类化合物具有酚羟基的特性，而 3-OH 取代基则赋予了它们最高的亲和力。然而，由于酚羟基的存在，这些化合物的物理化学性质通常使它们不适合体内应用，因为这会导致较差的药代动力学特性。我们合成了一种新型的二苯并氮杂卓衍生物，在 C(2)和 C(3)之间用亚甲二氧基取代了 3-OH 基团。新合成的衍生物 3 表现出与先导化合物 LE404 相似的高亲和力，对所有多巴胺受体亚型均表现出纳摩尔级的亲和力。其溴化衍生物 4 尽管亲和力下降了约五倍，但对除 D(4) 以外的所有多巴胺受体仍表现出纳摩尔级的亲和力。在功能性 Ca(2+)测定中，化合物 3 和 4 均被发现对多巴胺受体具有拮抗作用。
