Opioid activities of D-Arg2-substituted tetrapeptides.
The antinociceptive effects and mechanisms of action of H-Tyr-D-Ala-Phe-Gly-OH, H-Tyr-D-Arg-Phe-Gly-OH and H-Tyr-D-Arg-Phe-sarcosine(Sar)-OH have been investigated. The ED50 values of these peptides were 510.0, 8.2 and 2.0 pmol, respectively, when administered i.c.v. in the mouse tail-pressure test (dermorphin = 5.7 pmol and morphine = 1.2 nmol). These activities were remarkably potent and relatively long lasting. Their IC50 values were 676.8, 23.1 and 6.6 nM, respectively (dermorphin = 3.75 and morphine = 214.3 nM) in the guinea pig isolated ileum assay, and 138.50, 5.25 and 1.10 nM, respectively (dermorphin = 3.80 and morphine = 28.00 nM) in the radioreceptor assay utilizing [3H]naloxone as the opioid receptor ligand. In the evaluation of their inhibitory effects to enkephalin-degrading enzymes, the IC50 values of H-Tyr-D-Arg-Phe-Gly-OH, H-Tyr-D-Arg-Phe-Sar-OH and H-Tyr-D-Ala-Phe-Gly-OH were 5.4, 14.5 and more than 50.0 microM, respectively (bestatin = 0.1 microM) against aminopeptidase and 1.18, 1.40 and more than 50.0 microM, respectively (captopril = 0.38 and D-Phe-2S-, 3R-3-amino-2-hydroxy-4-phenylbutanoic acid = more than 100 microM) against the cleaving enzymes of enkephalin at its Gly3-Phe4 bond. The authors suggest that the marked antinociceptive potency of H-Tyr-D-Arg-Phe-Gly-OH and H-Tyr-D-Arg-Phe-Sar-OH is mainly due to high opioid receptor affinity. Their inhibitory effects on enkephalin-degrading enzymes and enzymatic stability also greatly contribute to their potent and long-lasting opioid activities.
D000818:Animals; D004745:Enkephalins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009294:Narcotics / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology*; D010147:Pain Measurement; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains
D004745:Enkephalins; D004791:Enzyme Inhibitors; D009294:Narcotics; D009842:Oligopeptides; C053416:tyrosyl-alanyl-phenylalanyl-glycine; C053417:tyrosyl-arginyl-phenylalanyl-glycine; C053418:tyrosyl-arginyl-phenylalanyl-sarcosine