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

A wide range of activities are induced by Lys when introduced at C-terminus of the delta-opioid Dmt-Tic pharmacophore through the alpha-amine group, including: improved delta-antagonism, mu-agonism and p-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 Dint-Tic through its side-chain amine group. All new compounds (1-9) displayed potent and selective delta-antagonism (MVD, pA(2) = 7.81-8.27), which was independent of the functionalized alpha-amine and carboxylic groups of C-terminal Lys. This behaviour suggests a direct application as a prototype intermediate, such as Boc-Dmt-Tic-epsilon-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 delta-antagonist Dmt-Tic and another opioid or biologically active non-opioid ligand. (c) 2007 Elsevier Ltd. All rights reserved.