Primofiore G, Da Settimo F, Taliani S, Marini A M, La Motta C, Novellino E, Greco G, Gesi M, Trincavelli L, Martini C
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
J Med Chem. 2000 Jan 13;43(1):96-102. doi: 10.1021/jm991131h.
A series of 3-substituted [1,2,4]triazino[4,3-c]benzimidazoles V were prepared and tested at the central benzodiazepine receptor (BzR). These compounds were designed as rigid analogues of the previously described N-benzylindolylglyoxylylamide derivatives IV. The title compounds V showed an affinity which depended directly on the presence of the N(10)-H group and an aromatic ring at position 3. Some of them elicited a 2- or 3-fold higher affinity with respect to that of the indolylglyoxylylamide derivatives IV (R = H). The GABA ratio and [(35)S]-tert-butylcyclophosphorothionate binding data revealed an efficacy profile of partial inverse agonists/antagonists for compounds 1c,e,f,j,k, and of a partial agonist for 2c. This last compound proved to be effective in antagonizing pentylenetetrazole-induced seizures in mice. Attempts were made to interpret the structure-affinity relationships of compounds V in the light of possible tautomeric equilibria involving the ligands.
制备了一系列3-取代的[1,2,4]三嗪并[4,3-c]苯并咪唑V，并在中枢苯二氮䓬受体（BzR）上进行了测试。这些化合物被设计为先前描述的N-苄基吲哚基乙醛酰胺衍生物IV的刚性类似物。标题化合物V显示出的亲和力直接取决于N(10)-H基团和3位芳环的存在。其中一些化合物相对于吲哚基乙醛酰胺衍生物IV（R = H）表现出高2至3倍的亲和力。GABA比率和[(35)S]-叔丁基环磷硫酰胺结合数据显示，化合物1c、e、f、j、k具有部分反向激动剂/拮抗剂的效能特征，而2c具有部分激动剂的效能特征。最后一种化合物在拮抗小鼠戊四氮诱导的惊厥方面被证明是有效的。尝试根据涉及配体的可能互变异构平衡来解释化合物V的结构-亲和力关系。
