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Design and synthesis of some aryloxyaryl semicarbazones and related compounds as novel anticonvulsants



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Two major pharmacological screening tests used to evaluate compounds for anticonvulsant activities are the maximal electroshock screen (MES) and the subcutaneous pentylenetetrazol (scPTZ) screen. The structural requirements for activity in the MES screen have been stated to be the presence of a large hydrophobic group which is in close proximity to at least two electron donor atoms. For activity in the scPTZ screen, a smaller, less hydrophobic group than is required for activity in the MES screen should be present near to a minimum of two electron donor atoms. Many currently available antiepileptic drugs possess a dicarboximide function (-CONHCO-) which may be associated with toxic side effects. Therefore, a number of compounds (aryl semicarbonazones and related analogs) were designed to be bereft of this group yet still fulfill the structural requirements for activity in the maximal electroshock screen (MES) and/or subcutaneous pentylenetetrazol (scPTZ) screen. Previous studies revealed that a number of aryl semicarbazones on oral administration to rats possessed significant anticonvulsant activity (ED50 figures in the 20-25 mg/kg range) in the MES screen. The principal aim of the study was to investigate the area around the postulated aryl binding site, with the main view of improving the potency. Ideally an ED50 of 1-3 mg/kg when administered orally to rats will be achieved. The biodata generated on these compounds may afford a clearer picture of the nature of the postulated binding site. A number of aryloryaryl semicarbazones and related compounds were synthesized and evaluated for anticonvulsant activities. After intraperitoneal injection to mice, the semicarbazones were examined in the MES, scPTZ and neurotoricity screens. The results indicated that greater protection was obtained in the MES test than the scPTZ screen. Quantitation of approximately one-third of the compounds revealed an average protection index of approximately 9. After oral administration to rats, a number of compounds displayed significant potencies in the MES screen (ED50 of 1-5 mg/kg) accompanied by very high protection indices. In fact over half the compounds had PI figures of greater than 100 and four were in excess of 200 and two compounds displayed protection indices greater than 300. A semicarbazons designated ADD 222036 (NC 1285/IV4) is the subject of a NIH "red book" and detailed pharmacological evaluations have been undertaken.





Doctor of Philosophy (Ph.D.)







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