CONFORMATIONAL-ANALYSIS OF POTENT AND VERY SELECTIVE DELTA-OPIOID DIPEPTIDE ANTAGONISTS

The delta selectivity and antagonism of peptides containing L-tetrahyd ro-3-isoquinoline carboxylic acid (Tie) in second position can be attr ibuted mainly to the Tyr-Tic unit, These properties can be further enh anced by substituting Tyr(1) with 2,6-dimethyl-L-tyrosyl (Dmt). Dmt-Ti c-NH2, Dmt-Tic-OH, Dmt-Tic-Ala-NH2 and Dmt-Tic-Ala-OH are all more act ive and/ or selective than the corresponding [Tyr(1)]-parent peptides, In fact the selectivities of Dmt-Tic-OH and Dmt-Tic-Ala-OH are the hi ghest ever recorded for opioid molecules, H-1 NMR spectra in a DMSO/wa ter mixture at 278 K reveal the presence of two similar conformers, ch aracterised by a cis or bass Dmt-Tic bond, in all four peptides, A det ailed conformational analysis in solution of Dmt-Tic-NH2 shows that th ese conformers have a shape very similar to that of the bioactive conf ormation of Tyr-Tic-NH2 and to that of naltrindole.