Evolution of the bifunctional lead mu agonist / delta antagonist containing the 2',6'-dimethyl-L-tyrosine-1,2,3,4-tetrahydroisoquinoline-3.carboxylic acid (Dmt-Tic) opioid pharmacophore

BALBONI, GIANFRANCO;SALVADORI S;TRAPELLA C;KNAPP B. I;BIDLACK J. M;LAZARUS L. H;PENG X;NEUMEYER J. L.

2010-01-01

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Abstract

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 μ agonist / δ antagonist, H-Dmt-Tic-Gly-NH-Bzl. 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, -CH(3), partially -NO(2), inactive -NH(2)) was found to give a more potent μ agonist / antagonist effect associated with a relatively unmodified δ antagonist activity (pA(2) = 8.28-9.02). Increasing the steric hindrance of the benzyl group (using diphenylmethyl and tetrahydroisoquinoline functionalities) substantially maintained the μ agonist and δ antagonist activities of the lead compound. Finally and quite unexpectedly D-Tic2, considered as a wrong opioid message now; inserted into the reference compound in lieu of L-Tic, provided a μ agonist / δ agonist better than our reference ligand (H-Dmt-Tic-Gly-NH-Ph) and was endowed with the same pharmacological profile.