The opioid mu agonist/delta antagonist DIPP-NH2[Psi] 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 expe cted to be analgesics with low propensity to produce tolerance and dependen ce. In an effort to strengthen the mu agonist component of the mixed mu ago nist/delta antagonist H-Tyr-Tic-Phe-Phe-NH2 (TIPP-NH2), analogues containin g structurally modified tyrosine residues in place of Tyr(1) were synthesiz ed. 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-N H2 (Tmt = N,2',6'-trimethyltyrosine) was a partial mu agonist/delta antagon ist and H-Tmt-Tic Psi[CH2NH]Phe-Phe-NH2 was a Psi antagonist/delta antagoni st. DIPP-NH2[Psi] showed binding affinities in the subnanomolar range for b oth mu and delta receptors in the rat brain membrane binding assays, thus r epresenting the first example of a balanced mu agonist/delta antagonist wit h high potency. In the rat tail flick test, DIPP-NH2[Psi] given icy produce d a potent analgesic effect (ED50 = 0.04 mu g), being about 3 times more po tent than morphine (ED50 = 0.11 mu g). It produced less acute tolerance tha n morphine but still a certain level of chronic tolerance. Unlike morphine, DIPP-NH2[Psi] produced no physical dependence whatsoever upon chronic admi nistration at high doses (up to 4.5 mu g/h) over a 7-day period. In conclus ion, DIPP-NH2[Psi] fulfills to a large extent the expectations based on the mixed Ca agonist/delta antagonist concept with regard to analgesic activit y and the development of tolerance and dependence.