Structure-activity relationships of unsaturated analogues of valproic acid.
The principal metabolite of valproic acid (VPA), 2-ene VPA, appears to share most of VPA's pharmacological and therapeutic properties while lacking its hepatotoxicity and teratogenicity, thus making it a useful lead compound for the development of safer antiepileptic drugs. Analogues of 2-ene VPA were evaluated for anticonvulsant activity in mice using the subcutaneous pentylenetetrazole test. Cyclooctylideneacetic acid exhibited a potency markedly exceeding that of VPA itself with only modest levels of sedation. Potency, as either ED50 or brain concentration, was highly correlated (r > 0.85) with volume and lipophilicity rather than with one of the shape parameters calculated by molecular modeling techniques, arguing against the existence of a specific receptor site. Instead, a role for the plasma membrane in mediating the anticonvulsant effect is suggested.
Palaty
J
J
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Abbott
F S
FS
D000818:Animals; D008401:Gas Chromatography-Mass Spectrometry; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D013329:Structure-Activity Relationship; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use
D014635:Valproic Acid