Comparison of opioid properties between D-Arg-containing dipeptides and tetrapeptides.
Since the D-Arg-containing dipeptides, H-Tyr-D-Arg-OMe (TDA) and H-Tyr(Et)-D-Arg-OMe, and D-Arg2-substituted dermorphin N-terminal tetrapeptide analogues, H-Tyr-D-Arg-Phe-Gly-OEt (TDAPG) and H-Tyr(Et)-D-Arg-Phe-Gly-OEt gave different pharmacological responses in vivo, opioid interaction and structure-activity relationships have been investigated in vitro. In the isolated guinea-pig ileum assay, the tetrapeptides were potently inhibitory, their activity markedly exceeding that of the dipeptides. In particular, the first tetrapeptide had twice the activity of morphine, while the potency of the dipeptides was less than one twentieth that of morphine. Also in the opioid receptor binding assay, tetrapeptides had a higher affinity than the dipeptides. IC50 values of tetrapeptides were 8.46 and 23.7 nM, respectively, which were lower than that of morphine. Ethylation of the Tyr residue of TDA much increased the opioid activity whereas that of TDAPG greatly decreased it. All peptides used were extremely stable to aminopeptidase-M and carboxypeptidase-Y and had an inhibitory effect on enkephalin (EK)-degrading enzymes. From these results, it appears that the effects of the tetrapeptides are due mainly to specific interaction with opioid receptors, whereas the dipeptides do not act specifically on the opioid receptors, but are involved in non-opioid mechanisms. The resistance to enzymes and inhibitory effect of the peptides used on the EK-degrading enzymes may also account for their potent and long-lasting opioid-like activities.
Sato
T
T
Department of Pharmaceutics, Tohoku College of Pharmacy, Sendai, Japan.
Sakurada
S
S
Sakurada
T
T
Kisara
K
K
Suzuki
K
K
D000595:Amino Acid Sequence; D000626:Aminopeptidases; D000818:Animals; D001120:Arginine; D018826:CD13 Antigens; D002268:Carboxypeptidases; D004151:Dipeptides / Q000494:pharmacology*; D006168:Guinea Pigs; D008297:Male; D008969:Molecular Sequence Data; D009020:Morphine / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects*; D013329:Structure-Activity Relationship
D004151:Dipeptides; D009842:Oligopeptides; D011957:Receptors, Opioid; D009020:Morphine; C042281:tyrosyl-arginyl-phenylalanyl-glycine ethyl ester; C042280:tyrosylarginine methyl ester; C042279:ethyltyrosylarginine methyl ester; C042282:ethyltyrosyl-arginyl-phenylalanyl-glycine ethyl ester; D001120:Arginine; D002268:Carboxypeptidases; D000626:Aminopeptidases; D018826:CD13 Antigens; C022633:serine carboxypeptidase