Assessment of substitution in the second pharmacophore of Dmt-Tic analogues

The Dmt-Tic pharmacophore exhibits potent δ-opioid receptor antagonism. Analogues with substitutions in the second pharmacophore with (1, 1′) or without a COOH function (2–9) were synthesized: several had high δ affinity (1′, 2, 7, and 9), but exhibited low to non-selectivity toward μ receptors similar to H-Dmt-Tic-amide and H-Dmt-Tic-ol. Functional bioactivity indicated high δ antagonism (pA2 7.4–7.9) (1′, 2, and 9) and modest μ agonism, pEC50 (6.1–6.3) (1′, 2, 8, and 9), but with Emax values analogous to dermorphin. These Dmt-Tic analogues with mixed δ antagonist/μ agonist properties would appear to be better candidates as analgesics than pure μ agonists.