Three peptides, cyclo[RGDRGD], cyclo[RGDRGd] (d = D-Asp), and the linear sequence RGDRGD, were prepared via solid phase syntheses. These were tested in binding assays based upon the alpha IIb/beta 3-fibrinogen and the alpha V beta 3-vitronectin interactions and found to be selective for the alpha V beta 3 integrin. The alpha V beta 3-vitronectin is important in bone regeneration, hence the compounds were also tested in an osteoclast regeneration assay; all three compounds, cyclo-[RGDRGD], cyclo[RGDRGd], and RGDRGD, showed modest activities. Molecular modeling, NMR, and CD studies were undertaken to elucidate the conformational preferences of cyclo-[RGDRGD], in aqueous solutions. Results from these studies strongly suggest that the molecule tends to adopt a type I beta-turn conformation with a relatively short distance between the Asp and Arg side chains. These observations are in harmony with the first correlations made between alpha V beta 3 selectivity and solution conformation for a peptide ligand (Pfaff, M.; et al. J. Biol. Chem. 1994, 269, 20233).