(Aryloxy)aryl semicarbazones and related compounds: a novel class of anticonvulsant agents possessing high activity in the maximal electroshock screen.
A number of (aryloxy)aryl semicarbazones and related compounds were synthesized and evaluated for anticonvulsant activities. After intraperitoneal injection to mice, the semicarbazones were examined in the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ), and neurotoxicity (NT) 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 (PI, i.e. TD50/ED50) 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 two were in excess of 300. The compounds were essentially inactive in the scPTZ and NT screens after oral administration to rats. Various compounds displayed greater potencies and PI figures in the mouse intraperitoneal and rat oral screens than three reference clinically used drugs. The data generated supported a binding site hypothesis. Quantitative structure-activity relationships indicated a number of physicochemical parameters which contributed to activity in the MES screen. X-ray crystallography of five compounds suggested the importance of certain interatomic distances and bond angles for activity in the mouse and rat MES screens.
Dimmock
J R
JR
College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Canada.
Puthucode
R N
RN
Smith
J M
JM
Hetherington
M
M
Quail
J W
JW
Pugazhenthi
U
U
Lechler
T
T
Stables
J P
JP
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004597:Electroshock; D006860:Hydrogen Bonding; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010433:Pentylenetetrazole / Q000008:administration & dosage; D051381:Rats; D012640:Seizures / Q000209:etiology / Q000517:prevention & control*; D012664:Semicarbazones / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; D012664:Semicarbazones; D010433:Pentylenetetrazole