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Opioid Peptide-Derived Analgesics

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Drug Addiction

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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 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.

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Authors and Affiliations

  1. Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada, H2W 1R7

    Peter W. Schiller

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  1. Peter W. Schiller
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Correspondence to Peter W. Schiller .

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Editors and Affiliations

  1. National Institute on Drug Abuse, Bethesda, MD, USA

    Rao S. Rapaka

  2. College of Medicine and Public Health, Ohio State University, Columbus, OH, USA

    Wolfgang Sadée

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© 2008 American Association of Pharmaceutical Scientists

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Schiller, P.W. (2008). Opioid Peptide-Derived Analgesics. In: Rapaka, R.S., Sadée, W. (eds) Drug Addiction. Springer, New York, NY. https://doi.org/10.1007/978-0-387-76678-2_22

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