Antagonists of fibrinogen at the GPIIb/IIIa receptor, which is the most abundant membrane protein on the platelet surface, are tinder active investigation as potential antithrombotics. The critical interaction between GPIIb/IIIa and fibrinogen can be inhibited by either linear or cyclic RGDS-containing peptides, which have been proved as lead compounds in the design of platelet aggregation inhibitors. In this study we present the design and construction of it new class of cyclic (S,S) non-RGD containing peptide sequences, using two Cys cis a structural scaffold for the development of antiaggregatory agents. The (S,S)-CDC- sequence was incorporated as a conformational constraint, in molecules bearing at least one positive charge with the general formula (S,S)XCDCZ, where X = Ac-Arg, Pro-Arg, Pro-Ser-Lys, and Pro-Ser-Arg, and Z = -NH2 and Arg-NH2. Investigation of the structure-function relationships was performed on the basis of (a) the local conformation induced by the (S,S)-CDC motif (b) the distance of the positively (R-C-zeta or K-N-zeta) and negatively (D-C-gamma) charged centers, (c) the presence of a second positive or negative charge on the molecule, and (d) the orientation of the basic and acidic side chains defined by, the pseudo dihedral angle (Pdo), which is formed by, the R-C-zeta, R-C-alpha, D-C-alpha, and D-C-gamma atoms in the case of (S,S)-RCDC and by the K-A K-C-alpha, D-C-alpha, and D-C-gamma atoms in the case of (S,S)-KCDC (C) 2001 John Wiley & Sons, Inc.