Structure−Activity Relationships of Pregabalin and Analogues That Target the α2-δ Protein
| Autor: | Thomas G. Heffner, Jack J. Kinsora, Jacob Bradley Schwarz, Ti Zhi-Su, David J. Wustrow, Leonard T. Meltzer, Thomas Richard Belliotti, Thomas Capiris, Andrew John Thorpe, Lawrence D. Wise, Mark L. Weber, Charles Taylor, Mark J. Field, Mark G. Vartanian, I.Victor Ekhato |
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| Rok vydání: | 2005 |
| Předmět: |
Male
Cyclohexanecarboxylic Acids Swine medicine.drug_class Pregabalin Alpha (ethology) CHO Cells Plasma protein binding In Vitro Techniques Pharmacology Anxiolytic Mice Structure-Activity Relationship Cricetulus Leucine In vivo Cricetinae Drug Discovery medicine Animals Structure–activity relationship Amines gamma-Aminobutyric Acid Analgesics Voltage-dependent calcium channel Chemistry Brain Transporter Rats Protein Subunits Anti-Anxiety Agents Biochemistry Mice Inbred DBA Amino Acid Transport System L Molecular Medicine Anticonvulsants Calcium Channels Gabapentin Protein Binding medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 48:2294-2307 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm049762l |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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