Belliotti Thomas R, Capiris Thomas, Ekhato I Victor, Kinsora Jack J, Field Mark J, Heffner Thomas G, Meltzer Leonard T, Schwarz Jacob B, Taylor Charles P, Thorpe Andrew J, Vartanian Mark G, Wise Lawrence D, Zhi-Su Ti, Weber Mark L, Wustrow David J
Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor Campus, Ann Arbor, MI, 48105, USA.
J Med Chem. 2005 Apr 7;48(7):2294-307. doi: 10.1021/jm049762l.
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.
普瑞巴林在临床前试验中表现出强大的活性，表明其具有潜在的抗癫痫、抗焦虑和抗痛觉过敏的临床疗效。它与电压门控钙通道的α(2)-δ亚基具有高亲和力结合，并且是系统L中性氨基酸转运体的底物。制备了一系列普瑞巴林类似物，并评估了它们与α(2)-δ的结合亲和力，这通过它们抑制[(3)H]加巴喷丁与猪脑膜结合的能力来证明，还评估了它们抑制[(3)H]亮氨酸摄取到CHO细胞中的效力，以此衡量它们在系统L转运体上与内源性底物竞争的能力。还在体内评估了化合物促进抗焦虑、镇痛和抗惊厥作用的能力。这些研究表明，α(2)-δ结合和系统L转运抑制存在不同的构效关系。然而，这两种相互作用似乎在这些化合物的体内特性中都起着重要作用。
