2',6'-dimethylphenylalanine (Dmp) can mimic the N-terminal Tyr in opioid peptides.
Substitution of 2',6'-dimethyltyrosine (Dmt) for the N-terminal Tyr in opioid peptides has recently been shown to be a promising tool for improving opioid receptor affinity and biological activity. We have also demonstrated that another unnatural amino acid, 2',6'-dimethylphenylalanine (Dmp), is not only an excellent substitute for Phe at position 3 but also can mimic the aromatic N-terminal Tyr residue in a micro opioid receptor-selective dermorphin analogue (YRFB: Tyr-D-Arg-Phe-betaAla-NH(2)). To further evaluate the value of Dmp in opioid peptides, we investigated Dmp(1)-substituted analogues of the delta receptor ligands, deltorphin II (DLT: Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH(2)) and enkephalin (ENK: Tyr-Gly-Gly-Phe-Leu). In the receptor binding assay, both [Dmp(1)]DLT and [Dmp(1)]ENK bound to the delta-receptor with high affinity and selectivity, and were nearly as effective as the parent peptides. The potency of the Dmp(1)-peptides on the MVD and GPI assays correlated well with the receptor binding affinity data. These results are in contrast to the tendency of corresponding Dmt(1)-analogues to have poor receptor selectivity. Taken together with the results with YRFB, we conclude that the Dmp(1)-peptide is superior to the corresponding Dmt(1)-peptide in its receptor selectivity. [Dmp(1)]DLT and [Dmp(1)]YRFB may serve as pharmacological tools for the studies of ligand recognition and opioid receptor signal transduction.
Sasaki
Yusuke
Y
Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Sasaki
Ai
A
Ariizumi
Tomio
T
Igari
Yukie
Y
Sato
Kohei
K
Kohara
Hirokazu
H
Niizuma
Hideko
H
Ambo
Akihiro
A
D000818:Animals; D004743:Enkephalin, Leucine / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D018716:Molecular Mimicry; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology*; D018847:Opioid Peptides / Q000737:chemistry*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D014443:Tyrosine / Q000737:chemistry*; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
C427023:2',6'-dimethylphenylalanine; D008024:Ligands; D009842:Oligopeptides; D018847:Opioid Peptides; D017465:Receptors, Opioid, delta; C060209:deltorphin II, Ala(2)-; D014443:Tyrosine; D010649:Phenylalanine; D004743:Enkephalin, Leucine