Further studies on the effect of lysine at the C-terminus of the Dmt-Tic opioid pharmacophore Original Research Article

A wide range of activities are induced by Lys when introduced at C-terminus of the δ-opioid Dmt-Tic pharmacophore through the α-amine group, including: improved δ-antagonism, μ-agonism and μ-antagonism. Here we report the synthesis of a new series of compounds with the general formula H-Dmt-Tic-NH-(CH2)4-CH(R)-R′ (R = -NH2, -NH-Ac, -NH-Z; R′ = CO-NH-Ph, -CO-NH-CH2-Ph, -Bid) in which Lys is linked to Dmt-Tic through its side-chain amine group. All new compounds (1–9) displayed potent and selective δ-antagonism (MVD, pA2 = 7.81–8.27), which was independent of the functionalized α-amine and carboxylic groups of C-terminal Lys. This behaviour suggests a direct application as a prototype intermediate, such as Boc-Dmt-Tic-ε-Lys(Z)-OMe, which could be successfully applied in the synthesis (after Z or methyl ester removal) of unique designed multiple ligands containing the pharmacophore of the quintessential δ-antagonist Dmt-Tic and another opioid or biologically active non-opioid ligand.