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Dermorphin tetrapeptide analogs as potent and long-lasting analgesics with pharmacological profiles distinct from morphine
Authors:Mizoguchi Hirokazu  Bagetta Giacinto  Sakurada Tsukasa  Sakurada Shinobu
Institution:a Department of Physiology and Anatomy, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
b Department of Pharmacobiology, University of Calabria, Arcavacata di Rende, Cosenza 87036, Italy
c First Department of Pharmacology, Daiichi College of Pharmaceutical Sciences, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan
Abstract:Dermorphin (Tyr-d-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) is a heptapeptide isolated from amphibian skin. With a very high affinity and selectivity for μ-opioid receptors, dermorphin shows an extremely potent antinociceptive effect. The structure-activity relationship studies of dermorphin analogs clearly suggest that the N-terminal tetrapeptide is the minimal sequence for agonistic activity at μ-opioid receptors, and that the replacement of the d-Ala2 residue with d-Arg2 makes the tetrapeptides resistant to enzymatic metabolism. At present, only a handful of dermorphin N-terminal tetrapeptide analogs containing d-Arg2 have been developed. The analogs show potent antinociceptive activity that is greater than that of morphine with various injection routes, and retain high affinity and selectivity for μ-opioid receptors. Interestingly, some analogs show pharmacological profiles that are distinct from the traditional μ-opioid receptor agonists morphine and d-Ala2,NMePhe4,Gly-ol5]enkephalin (DAMGO). These analogs stimulate the release of dynorphins through the activation of μ-opioid receptors. The activation of κ-opioid receptors by dynorphins is suggested to reduce the side effects of μ-opioid receptor agonists, e.g., dependence or antinociceptive tolerance. The dermorphin N-terminal tetrapeptide analogs containing d-Arg2 may provide a new target molecule for developing novel analgesics that have fewer side effects.
Keywords:Dermorphin analog  Analgesics  μ-Opioid receptor  κ-Opioid receptor  Dynorphins  Dependence
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