Toja E, Tarzia G, Barone D, Luzzani F, Gallico L
J Med Chem. 1985 Sep;28(9):1314-9. doi: 10.1021/jm00147a034.
A series of 3,6-disubstituted pyridazino[4,3-c]isoquinolines were synthesized and tested for their ability to inhibit the binding of [3H]diazepam to rat brain receptors in vitro. Compounds bearing a phenyl, 4-methoxyphenyl, or methyl group at position 3 and a dialkylamino group at position 6 showed the highest affinity in the binding assay and were subsequently evaluated for their anticonflict and anticonvulsant effects. All of these compounds (5a-1 and 5q) were active in the Vogel rat conflict procedure, but none prevented convulsions in mice induced either by metrazol or bicuculline. 3-Phenyl-6-pyrrolidinylpyridazino[4,3-c]isoquinoline (5d) with a Ki = 11.4 nM in the binding assay exhibited the best potency in the anticonflict assay (MED 5 mg/kg ip) and did not produce neuromuscular impairment at the highest dose tested (50 mg/kg ip).
合成了一系列3,6 - 二取代的哒嗪并[4,3 - c]异喹啉，并对其在体外抑制[3H]地西泮与大鼠脑受体结合的能力进行了测试。在3位带有苯基、4 - 甲氧基苯基或甲基且在6位带有二烷基氨基的化合物在结合试验中表现出最高的亲和力，随后对其抗冲突和抗惊厥作用进行了评估。所有这些化合物（5a - 1和5q）在Vogel大鼠冲突试验中均有活性，但均不能预防由戊四氮或荷包牡丹碱诱导的小鼠惊厥。在结合试验中Ki = 11.4 nM的3 - 苯基 - 6 - 吡咯烷基哒嗪并[4,3 - c]异喹啉（5d）在抗冲突试验中表现出最佳效力（腹腔注射半数有效剂量5 mg/kg），并且在测试的最高剂量（腹腔注射50 mg/kg）下未产生神经肌肉损伤。
