Calcium channel alpha2-delta type 1 subunit is the major binding protein for pregabalin in neocortex, hippocampus, amygdala, and spinal cord: An ex vivo autoradiographic study in alpha2-delta type 1 genetically modified mice

摘要: Pregabalin is a synthetic amino acid compound effective in clinical trials for the treatment of post-herpetic neuralgia, diabetic peripheral neuropathy, generalized anxiety disorder and adjunctive therapy partial seizures epilepsy. However, mechanisms by which pregabalin exerts its therapeutic effects are not yet completely understood. In vitro studies have shown that binds with high affinity to alpha(2)-delta (alpha(2)-delta) subunits (Type 1 2) voltage-gated calcium channels. To assess whether Type major central nervous system (CNS) binding protein vivo, mutant mouse an arginine-to-alanine mutation at 217 (R217A mutation) was generated. Previous site-directed mutagenesis revealed R217A dramatically reduces vitro. this autoradiographic analysis mice, we show substantially specific CNS regions known preferentially express protein, notably neocortex, hippocampus, basolateral amygdala spinal cord. robust throughout where 2 subunit mRNA abundant, such as cerebellum. These findings, conjunction prior data, provide evidence channels CNS. Moreover, distinct localization mutation-resistant (assumed be brain areas subserving different functions suggests identification subunit-specific ligands could further enhance pharmacologic specificity.