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