The opioid μ agonist/δ antagonist DIPP-NH2[Ψ] produces a potent analgesic effect, no physical dependence, and less tolerance than morphine in rats

Opioid compounds with mixed CL agonist/delta antagonist properties are expected to be analgesics with low propensity to produce tolerance and dependence. In an effort to strengthen the mu agonist component of the mixed mu agonist/delta antagonist H-Tyr-Tic-Phe-Phe-NH2 (TIPP-NH2), analogues containing structurally modified tyrosine residues in place of Tyr(1) were synthesized. Among the prepared compounds, H-Dmt-Tic-Phe-Phe-NH2 (DIPP-NH2; Dmt = 2',6'-dimethyl-tyrosine) and H-Dmt-Tic Psi[CH2NH]Phe-Phe-NH2 (DIPP-NH2[Psi]) retained a mixed mu agonist/delta antagonist profile, as determined in the guinea pig ileum and mouse vas deferens assays, whereas H-Tmt-Tic-Phe-Phe-NH2 (Tmt = N,2',6'-trimethyltyrosine) was a partial mu agonist/delta antagonist and H-Tmt-Tic Psi[CH2NH]Phe-Phe-NH2 was a Psi antagonist/delta antagonist. DIPP-NH2[Psi] showed binding affinities in the subnanomolar range for both mu and delta receptors in the rat brain membrane binding assays, thus representing the first example of a balanced mu agonist/delta antagonist with high potency. In the rat tail flick test, DIPP-NH2[Psi] given icy produced a potent analgesic effect (ED50 = 0.04 mu g), being about 3 times more potent than morphine (ED50 = 0.11 mu g). It produced less acute tolerance than morphine but still a certain level of chronic tolerance. Unlike morphine, DIPP-NH2[Psi] produced no physical dependence whatsoever upon chronic administration at high doses (up to 4.5 mu g/h) over a 7-day period. In conclusion, DIPP-NH2[Psi] fulfills to a large extent the expectations based on the mixed Ca agonist/delta antagonist concept with regard to analgesic activity and the development of tolerance and dependence.