| Autor: |
Belliotti, T. R., Capiris, T., Ekhato, I. V., Kinsora, J. J., Field, M. J., Heffner, T. G., Meltzer, L. T., Schwarz, J. B., Taylor, C. P., Thorpe, A. J., Vartanian, M. G., Wise, L. D., Zhi-Su, T., Weber, M. L., Wustrow, D. J. |
| Zdroj: |
Journal of Medicinal Chemistry; April 2005, Vol. 48 Issue: 7 p2294-2307, 14p |
| Abstrakt: |
Pregabalin exhibits robust activity in preclinical assays indicative of potential antiepileptic, anxiolytic, and antihyperalgesic clinical efficacy. It binds with high affinity to the α2-δ 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 α2-δ 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 α2-δ binding and system L transport inhibition. However, both interactions appear to play an important role in the in vivo profile of these compounds. |
| Databáze: |
Supplemental Index |
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