delta-Selective antagonism of [L-Tic2]-peptides, including the simple dipeptide Tyr-L-Tic-NH2, is linked to the Tyr-Tic-"recognition site". In order to gain further information on the conformational preferences of the Tyr-Tic-moiety we have undertaken a structural study of a cyclic analog, the diketopiperazine of Tyr-Tic. A conformational study of cyclo[-Tyr-Tic-], that is almost devoid of opioid activity, can also be useful to discriminate between the role of the two aromatic rings and of the basic nitrogen in determining antagonism. The structure of cyclo[-Tyr-Tic-] has been solved in a DMSO/water solution at 278 K by NMR spectroscopy and in the solid state by X-ray diffraction methods. The two informations are almost identical, with an arrangement of the aromatic rings rather different from that of the putative bioactive conformation of the parent linear dipeptide. This difference points to the importance of conformational effects and is in agreement with the hypothesis that the positive center may be not essential for antagonism.