1. Structure-activity relationships of pregabalin and analogues that target the alpha(2)-delta protein.
- Author
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Belliotti TR, Capiris T, Ekhato IV, Kinsora JJ, Field MJ, Heffner TG, Meltzer LT, Schwarz JB, Taylor CP, Thorpe AJ, Vartanian MG, Wise LD, Zhi-Su T, Weber ML, and Wustrow DJ
- Subjects
- Amines antagonists & inhibitors, Amines metabolism, Analgesics chemistry, Analgesics pharmacology, Animals, Anti-Anxiety Agents chemistry, Anti-Anxiety Agents pharmacology, Anticonvulsants chemistry, Anticonvulsants pharmacology, Brain metabolism, CHO Cells, Cricetinae, Cricetulus, Cyclohexanecarboxylic Acids antagonists & inhibitors, Cyclohexanecarboxylic Acids metabolism, Gabapentin, In Vitro Techniques, Leucine antagonists & inhibitors, Leucine metabolism, Male, Mice, Mice, Inbred DBA, Pregabalin, Protein Binding, Protein Subunits metabolism, Rats, Structure-Activity Relationship, Swine, gamma-Aminobutyric Acid chemistry, gamma-Aminobutyric Acid metabolism, gamma-Aminobutyric Acid pharmacology, Amino Acid Transport System L metabolism, Analgesics chemical synthesis, Anti-Anxiety Agents chemical synthesis, Anticonvulsants chemical synthesis, Calcium Channels metabolism, gamma-Aminobutyric Acid analogs & derivatives, gamma-Aminobutyric Acid chemical synthesis
- Abstract
Pregabalin exhibits robust activity in preclinical assays indicative of potential antiepileptic, anxiolytic, and antihyperalgesic clinical efficacy. It binds with high affinity to the alpha(2)-delta 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 alpha(2)-delta binding affinity as demonstrated by their ability to inhibit binding of [(3)H]gabapentin to pig brain membranes and for their potency to inhibit the uptake of [(3)H]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 alpha(2)-delta binding and system L transport inhibition. However, both interactions appear to play an important role in the in vivo profile of these compounds.
- Published
- 2005
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