Comparative specificity of platelet IIb3 integrin antagonists. J Pharmacol Exp Ther 296: 690–606

Abstract

ABSTRACT Several platelet ␣ IIb ␤ 3 integrin antagonists have been designed as preventive agents against the formation of arterial thrombi. Although the potency of these compounds in inhibiting platelet aggregation is in the nanomolar range, their specificity on other integrins that can bind ligands through an arginine-glycineaspartic acid (RGD) motif is far from being well established. For instance, some cyclic RGD peptides can also interact with ␣ v ␤ 3 integrin. We used a novel pharmacological assay, based on SDS-stable interaction between 125 I-echistatin and RGD-dependent integrins, to evaluate the specificity of several RGD compounds on integrins present on rat cardiac fibroblasts and human skin fibroblasts. None of the RGD peptidomimetics tested (L-734,217, lamifiban, Ro 44-3888, SR 121566A, BIBU-52, XV459) could interact with either ␣ v ␤ 3 and ␣ 8 ␤ 1 on rat fibroblasts or with ␣ v ␤ 3 and ␣ v ␤ 1 on human fibroblasts. Cyclic RGD peptides showed some potency (3-80 M) on rat and human integrins with an ␣ v subunit. We also compared the potency of these compounds on platelets. All RGD compounds demonstrated IC 50 between 0.6 and 530 nM on basal human platelets. Activation of the receptor with thrombin resulted in a 2-to 60-fold increase in potency, with L-734,217 and BIBU-52 showing the largest difference. On basal and thrombin-activated rat platelets, only eptifibatide, DMP728, and XJ735 could displace 125 I-echistatin (IC 50 Ϸ 0.1-1.5 M). These results indicate that RGD peptidomimetics have a specificity limited to ␣ IIb ␤ 3 integrin, whereas cyclic RGD peptides can also interact with other RGD-dependent integrins, particularly those of the ␣ v subunit family