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. 2005 Oct 14;7(3):E560–E565. doi: 10.1208/aapsj070356

Opioid peptide-derived analgesics

Peter W Schiller 1,✉
PMCID: PMC2751258  PMID: 16353933

Abstract

Two recent developments of opioid peptide-based analgesics are reviewed. The first part of the review discusses the dermorphin-derived, cationic-aromatic tetrapeptide H-Dmt-D-Arg-Phe-Lys-NH2 ([Dmt1]DALDA, where Dmt indicates 2′,6′-dimethyltyrosine), which showed subnanomolar μ receptor binding affinity, extraordinary μ receptor selectivity, and high μ agonist potency in vitro. In vivo, [Dmt1]DALDA looked promising as a spinal analgesic because of its extraordinary antinociceptive effect (3000 times more potent than morphine) in the mouse tail-flick assay, long duration of action (4 times longer than morphine), and lack of effect on respiration. Unexpectedly, [Dmt1]DALDA also turned out to be a potent and long-acting analgesic in the tail-flick test when given subcutaneously (s.c.), indicating that it is capable of crossing the blood-brain barrier. Furthermore, little or no cross-tolerance was observed with s.c. [Dmt1]DALDA in morphine-tolerant mice. The second part of the review concerns the development of mixed μ agonist/δ antagonists that, on the basis of much evidence, are expected to be analgesics with a low propensity to produce tolerance and physical dependence. The prototype pseudopeptide H-Dmt-TicΨ[CH2NH]Phe-Phe-NH2 (DIPP-NH2[Ψ], where Tic indicates 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) showed subnanomolar μ and δ receptor binding affinities and the desired μ agonist/δ antagonist profile in vitro. DIPP-NH2[Ψ] produced a potent analgesic effect after intracerebroventricular administration in the rat tail-flick assay, no physical dependence, and less tolerance than morphine. The results obtained with DIPP-NH2[Ψ] indicate that mixed μ agonist/δ antagonists look promising as analgesic drug candidates, but compounds with this profile that are systemically active still need to be developed.

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