| Summary: | Vaiproic acid (VPA) is a versatile clinical antiepileptic drug which is also
characterized by rare but potentially fatal side effects such as hepatotoxicity and
teratogenicity. Its principal metabolite, the α,β-unsaturated acid 2-ene VPA, appears to share
most of VPA’s therapeutic properties while lacking its toxicity and is thus a useful lead
compound for the development of safer antiepileptic drugs. The objectives of this thesis were
to shed some light on the anticonvulsant properties of 2-ene VPA analogues by an
investigation of their influences on GABA metabolism and membrane fluidity.
A group of α,β-unsaturated acids were synthesized by established methods or minor
modifications thereof. The compounds were then evaluated for anticonvulsant activity in
mice using the subcutaneous pentylenetetrazole test. Cyclooctylideneacetic acid (compound
17) exhibited a potency markedly exceeding that of VPA itself with no more than modest
levels of sedation. Potency, as log(ED5O), was highly correlated with both volume and
lipophilicity rather than with one of the shape parameters calculated by molecular modelling
techniques, arguing against the existence of a specific receptor site. These relationships
remained essentially intact when ED5O was replaced with the brain concentration of the drug
15 min following an ED5O dose.
Subsequent studies focused on the properties of nerve terminals from whole brain
homogenates prepared from mice administered an ED5O dose of each drug. GABA levels
were generally found to be elevated, supporting the central role of this neurotransmitter in the
anticonvulsant properties of VPA and its analogues. Selectivity for regional or functional
pools of GABA was suggested as a cause for the variability. The activity of GABA’s
synthesizing enzyme glutamate decarboxylase was mostly unchanged but some drugs, notably
compound 17, showed a significant decrease in activity compared to the control. These
influences on GAD activity were unrelated to the extent of binding of the enzyme’s co-factor,
pyridoxal 5¹-phosphate, following in vivo administration of VPA, 2-ene VPA and compound
17. Finally, the activity of the GAD was found to be inhibited in a non-competitive manner
by compound 17 with Ki =9 mM. === Pharmaceutical Sciences, Faculty of === Graduate
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