Dermorphin tetrapeptide analogs as potent and long-lasting analgesics with pharmacological profiles distinct from morphine.
Dermorphin (Tyr-d-Ala-Phe-Gly-Tyr-Pro-Ser-NH(2)) 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-Ala(2) residue with d-Arg(2) makes the tetrapeptides resistant to enzymatic metabolism. At present, only a handful of dermorphin N-terminal tetrapeptide analogs containing d-Arg(2) 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-Ala(2),NMePhe(4),Gly-ol(5)]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-Arg(2) may provide a new target molecule for developing novel analgesics that have fewer side effects.
Department of Physiology and Anatomy, Tohoku Pharmaceutical University, Aoba-ku, Sendai 981-8558, Japan.
Hirokazu
H
Mizoguchi
Giacinto
G
Bagetta
Tsukasa
T
Sakurada
Shinobu
S
Sakurada
D000701:Analgesics, Opioid / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D006801:Humans; D009020:Morphine / Q000009:adverse effects / Q000494:pharmacology*; D009842:Oligopeptides / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D018847:Opioid Peptides / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*
D000701:Analgesics, Opioid; D009842:Oligopeptides; D018847:Opioid Peptides; C030058:dermorphin; D009020:Morphine