Effect of lysine at C-terminus of the Dmt-Tic opioid pharmacophore

Substitution of Gly with side-chain-protected or unprotected Lys in lead compounds containing the opioid pharmacophore Dmt-Tic [H-Dmt-Tic-Gly-NH-CH2-Ph, í agonist/ä antagonist; H-Dmt-Tic-Gly-NH-Ph, í agonist/ä agonist; and H-Dmt-Tic-NH-CH2-Bid, ä agonist (Bid ) 1H-benzimidazole-2-yl)] yielded a new series of compounds endowed with distinct pharmacological activities. Compounds (1-10) included high ä- (Ki ä ) 0.068-0.64 nM) and í-opioid affinities (Ki í ) 0.13-5.50 nM), with a bioactivity that ranged from í-opioid agonism {10, H-Dmt-Tic-NH-CH[(CH2)4-NH2]-Bid (IC50 GPI ) 39.7 nM)} to a selective í-opioid antagonist [3, H-Dmt-Tic-Lys-NH-CH2-Ph (pA2 í ) 7.96)] and a selective ä-opioid antagonist [5, H-Dmt-Tic-Lys(Ac)-NH-Ph (pA2 ä ) 12.0)]. The presence of a Lys linker provides new lead compounds in the formation of opioid peptidomimetics containing the Dmt-Tic pharmacophore with distinct agonist and/ or antagonist properties.