Comparative specificity of platelet alpha(IIb)beta(3) integrin antagonists

Several platelet alpha (IIb)beta (3) integrin antagonists have been designe d 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 ligand s through an arginine-glycine-aspartic acid (RGD) motif is far from being w ell established. For instance, some cyclic RGD peptides can also interact w ith alpha (v)beta (3) integrin. We used a novel pharmacological assay, base d on SDS-stable interaction between I-125-echistatin and RGD-dependent inte grins, to evaluate the specificity of several RGD compounds on integrins pr esent on rat cardiac fibroblasts and human skin fibroblasts. None of the RG D peptidomimetics tested (L-734,217, lamifiban, Ro 44-3888, SR 121566A, BIB U-52, XV459) could interact with either alpha (v)beta (3) and alpha (8)beta (1) on rat fibroblasts or with alpha (v)beta (3) and alpha (v)beta (1) on human fibroblasts. Cyclic RGD peptides showed some potency (3-80 muM) on ra t and human integrins with an alpha (v) subunit. We also compared the poten cy of these compounds on platelets. All RGD compounds demonstrated IC50 bet ween 0.6 and 530 nM on basal human platelets. Activation of the receptor wi th 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-activate d rat platelets, only eptifibatide, DMP728, and XJ735 could displace I-125- echistatin (IC50 approximate to 0.1-1.5 muM). These results indicate that R GD peptidomimetics have a specificity limited to alpha (IIb)beta (3) integr in, whereas cyclic RGD peptides can also interact with other RGD-dependent integrins, particularly those of the alpha (v) subunit family.