Drug Addiction pp 357-366 | Cite as

Opioid Peptide-Derived Analgesics

  • Peter W. Schiller


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 longacting 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.


Opioid Receptor Morphine Tolerance Delta Opioid Receptor Receptor Binding Affinity Agonist Potency 
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Copyright information

© American Association of Pharmaceutical Scientists 2008

Authors and Affiliations

  1. 1.Laboratory of Chemical Biology and Peptide ResearchClinical Research Institute of MontrealMontrealCanada

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