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Structure-activity relationships of pregabalin and analogues that target the alpha(2)-delta protein

Structure-activity relationships of pregabalin and analogues that target the alpha(2)-delta protein

  1. staples
    Pregabalin exhibits robust activity in preclinical assays indicative of potential antiepileptic, anxiolytic, and antihyperalgesic clinical efficacy. It binds with high affinity to the R2-ä subunit of voltage-gated calcium channels and is a substrate of the system L neutral amino acid transporter. A series of pregabalin analogues were prepared and evaluated for their R2-ä binding affinity as demonstrated by their ability to inhibit binding of [3H]gabapentin to pig brain membranes and for their potency to inhibit the uptake of [3H]leucine into CHO cells, a measure of their ability to compete with the endogenous substrate at the system L transporter. Compounds were also assessed in vivo for their ability to promote anxiolytic, analgesic, and anticonvulsant actions. These studies suggest that distinct structure activity relationships exist for R2-ä binding and system L transport inhibition. However, both interactions appear to play an important role in the in vivo profile of these compounds.