Dimmock J R, Sidhu K K, Thayer R S, Mack P, Duffy M J, Reid R S, Quail J W, Pugazhenthi U, Ong A, Bikker J A
College of Pharmacy, University of Saskatchewan, Saskatoon, Canada.
J Med Chem. 1993 Aug 6;36(16):2243-52. doi: 10.1021/jm00068a001.
Various semicarbazones derived from aryl aldehydes, phenylalkyl aldehydes, and phenylalkyl ketones as well as some related compounds were evaluated for anticonvulsant activity. Most of the compounds displayed anticonvulsant activity in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens accompanied by neurotoxicity when given to mice by the intraperitoneal route. However quantitative data revealed protection indices (TD50/ED50) of less than 4 in general. Oral administration of the compounds to rats led to excellent potency in the MES screen accompanied by high protection indices while virtually no activity in the scPTZ test was displayed. These observations support the theory that one large hydrophobic group (in this case the aryl ring) and two electron donor atoms (present in the semicarbazono group) are requirements for protection in the MES screen. In general, the semicarbazones had rapid onsets of action, and one of the ways in which these compounds displayed their anticonvulsant activity is likely to be interaction with chloride channels. Empirical and semiempirical conformational calculations indicated that certain molecular fragments and hydrophobicity of these molecules affect bioactivity.
对源自芳基醛、苯烷基醛、苯烷基酮以及一些相关化合物的各种氨基脲进行了抗惊厥活性评估。大多数化合物在最大电休克（MES）和皮下注射戊四氮（scPTZ）筛选试验中表现出抗惊厥活性，但通过腹腔注射给小鼠时会伴有神经毒性。然而，定量数据显示，一般保护指数（TD50/ED50）小于4。给大鼠口服这些化合物在MES筛选试验中显示出优异的效力，同时具有高保护指数，但在scPTZ试验中几乎没有活性。这些观察结果支持了这样一种理论，即在MES筛选试验中起保护作用需要一个大的疏水基团（在这种情况下为芳环）和两个供电子原子（存在于氨基脲基团中）。一般来说，氨基脲起效迅速，这些化合物表现出抗惊厥活性的一种方式可能是与氯离子通道相互作用。经验性和半经验性构象计算表明，这些分子的某些分子片段和疏水性会影响生物活性。
