Abstracts

Rationale: Pregabalin (Lyrica ) is approved in the U.S. as an adjunctive treatment for partial epilepsy. Pregabalin binds with high affinity to the ?₂?₁ and ?₂?₂ proteins of the voltage sensitive calcium channel. Mutagenesis studies have shown that a point mutant in ?₂?₁ (R217A) or in ?₂?₂ (R279A) removes binding of pregabalin to the ?₂?₁ or ?₂?₂ proteins. Methods: These mutations have been introduced into mice to generate animals in which the wild type protein has been replaced by the mutant protein. C57BL/6N mice which are congenic for either the R217A mutation in ?₂?₁ or the R279A mutation in ?₂?₂ were tested in the mouse maximal electroshock model to determine whether the anticonvulsant activity of pregabalin changed by the mutations. Results: Results show that the anticonvulsant activity of pregabalin in this model is eliminated in the ?₂?₁ mutants, but is identical to wild type in the ?₂?₂ mutants. Phenytoin is active in animals carrying either mutation. Conclusions: These data show that the anticonvulsant activity of pregabalin arises from its interaction with ?₂?₁ subunits, not ?₂?₂ subunits. Funded by Pfizer Inc.