2',6'-Dimethylphenylalanine (Dmp) Can Mimic the N-Terminal Tyr in Opioid Peptides(Medicinal Chemistry)

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概要

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• 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 μ opioid receptor-selective dermorphin analogue (YRFB: Tyr-D-Arg-Phe-βAla-NH_2). To further evaluate the value of Dmp in opioid peptides, we investigated Dmp^1-substituted analogues of the δ receptor ligands, deltorphin II (DLT: Tyr-o-Ala-Phe-Glu-Val-Val-Gly-NH_2) and enkephalin (ENK: Tyr-Gly-Gly-Phe-Leu). In the receptor binding assay, both [Dmp'lDLT and [Dmp^1]ENK bound to the δ-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'-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.

• 公益社団法人日本薬学会の論文
• 2004-02-01

著者

• AMBO Akihiro

  Tohoku Pharmaceutical University

• SASAKI Yusuke

  Tohoku Pharmaceutical University

• Ambo A

  Tohoku Pharmaceutical University

• Sasaki Y

  Tohoku Pharmaceutical University

• Shimohigashi Yasuyuki

  Laboratory Of Structure-function Biochemistry Department Of Molecular Chemistry Graduate School Of S

• NIIZUMA Hideko

  Tohoku Pharmaceutical University

• Niizuma H

  Tohoku Pharmaceutical University

• Sasaki Ai

  Tohoku Pharmaceutical University

• KOHARA Hirokazu

  Tohoku Pharmaceutical University

• ARIIZUMI Tomio

  Tohoku Pharmaceutical University

• IGARI Yukie

  Tohoku Pharmaceutical University

• SATO Kohei

  Tohoku Pharmaceutical University

• Sasaki Yusuke

  Tohoku College Of Pharmacy

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