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Unsaturated analogues of valproic acid : structure activity relationships and interaction with gaba metabolism

University of British Columbia

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.

Thesis/Dissertation

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2009-06-11

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http://hdl.handle.net/2429/8954

Pharmaceutical Sciences

University of British Columbia

UBCV

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