Evolution of the Bifunctional Lead μ Agonist/δ Antagonist Containing the 2′,6′-Dimethyl-L-tyrosine-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acid (Dmt-Tic) Opioid Pharmacophore

Based on a renewed importance recently attributed to bi- or multifunctional opioids, we report the synthesis and pharmacological evaluation of some analogues derived from our lead mu agonistic/delta antagonist, H-Dmt-Tic-Gly-NH-Bzl (Dmt = 2',6'-dimethyl-L-tyrosine, Tic = 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, Bzl = benzyl). Our previous studies focused on the importance of the C-teminal benzyl function in the induction of such bifunctional activity. The introduction of some substituents in the para position of the phenyl ring (-Cl, -CH3, partially -NO2, inactive -NH2) was found to give a more potent mu agonist/antagonist effect associated with a relatively unmodified delta antagonist activity (pA(2) = 8.28-9.02). Increasing the steric hindrance of the benzyl group (using diphenylmethyl and tetrahydroisoquinoline functionalities) substantially maintained the mu agonist and delta antagonist activities of the lead compound. Finally and quite unexpectedly D-Tic(2), considered as a wrong opioid message now, inserted into the reference compound in lieu of L-Tic provided a mu agonist/delta agonist better than our reference ligand (H-Dmt-Tic-Gly-NH-Ph; Ph = phenyl) and was endowed with the same pharmacological profile.