Biological Properties of Opioid Peptides Replacing Tyr at Position 1 by 2,6-Dimethyl-Tyr.

Sasaki, Yoshiyuki; Suto, Takuya; Ambo, Akihiro; Ouchi, Hidekazu; Yamämoto, Yasushi

doi:10.1248/cpb.47.1506

Cited by 51 publications

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“…13,17) For the synthesis of DLT analogues (1, 2), an N-terminal Dmp residue was incorporated using Fmoc-Dmp racemate.…”

Section: Methodsmentioning

confidence: 99%

“…15) Fmoc-Dmp or Boc-Dmt used was prepared by the method reported previously. 13,17) For the synthesis of DLT analogues (1, 2), an N-terminal Dmp residue was incorporated using Fmoc-Dmp racemate. 17) Cleavage of the peptides from the resin was carried out by treatment with TFA-phenol (95 : 5) at room temperature for 1 h. The diastereoisomeric peptides (1, 2) were separated using medium-pressure HPLC, as described previously.…”

Section: Peptide Synthesismentioning

confidence: 99%

“…Recent structure-activity studies have shown that introduction of the artificial amino acid 2Ј,6Ј-dimethyltyrosine (Dmt) in place of the N-terminal Tyr residue is a promising way to greatly enhance receptor affinity and functional potency. [2][3][4][5][6][7][8][9][10][11][12][13] However the Dmt 1 -substitution generally has resulted in low receptor selectivity due to markedly enhanced affinity toward the concomitant receptor vs. the preferred receptor. 3,6,8,12,13) We have recently demonstrated that 2Ј,6Ј-dimethylphenylalanine (Dmp) is an excellent surrogate for the Phe at position 3 in Tyr-D-Arg-Phe-bAla-NH 2 (YRFB), 14) endomorphin 2, 15) dermorphin, 16) and deltorphin II.…”

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confidence: 99%

“…[2][3][4][5][6][7][8][9][10][11][12][13] However the Dmt 1 -substitution generally has resulted in low receptor selectivity due to markedly enhanced affinity toward the concomitant receptor vs. the preferred receptor. 3,6,8,12,13) We have recently demonstrated that 2Ј,6Ј-dimethylphenylalanine (Dmp) is an excellent surrogate for the Phe at position 3 in Tyr-D-Arg-Phe-bAla-NH 2 (YRFB), 14) endomorphin 2, 15) dermorphin, 16) and deltorphin II. 16) We also demonstrated that Dmp can be substituted for the N-terminal Tyr residue in the m receptor-selective agonists YRFB 14) and endomorphin 2 15) without a substantial decrease in m receptor affinity and selectivity.…”

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confidence: 99%

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

Sasaki

Ariizumi

et al. 2004

Biological & Pharmaceutical Bulletin

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In opioid peptides, the N-terminal Tyr and the Phe at position 3 or 4 are aromatic residues that are necessary for the opioid activity. Recent structure-activity studies have shown that introduction of the artificial amino acid 2Ј,6Ј-dimethyltyrosine (Dmt) in place of the N-terminal Tyr residue is a promising way to greatly enhance receptor affinity and functional potency. [2][3][4][5][6][7][8][9][10][11][12][13] However the Dmt 1 -substitution generally has resulted in low receptor selectivity due to markedly enhanced affinity toward the concomitant receptor vs. the preferred receptor. 3,6,8,12,13) We have recently demonstrated that 2Ј,6Ј-dimethylphenylalanine (Dmp) is an excellent surrogate for the Phe at position 3 in Tyr-D-Arg-Phe-bAla-NH 2 (YRFB), 14) endomorphin 2, 15) dermorphin, 16) and deltorphin II. 16) We also demonstrated that Dmp can be substituted for the N-terminal Tyr residue in the m receptor-selective agonists YRFB 14) and endomorphin 2 15) without a substantial decrease in m receptor affinity and selectivity. In particular, the Dmp 1 -YRFB had somewhat higher m receptor affinity than the parent peptide, although its in vitro bioactivity was slightly lower.14) These findings are interesting because the Dmp 1 -peptides lack a phenolic hydroxyl group at the N-terminal side chain. More importantly, these Dmp 1 -analogues had high m receptor selectivity. These findings contrast with the effects of Dmt 1 -substitution. In the present study, we report further analogues of the d opioid receptor-selective ligands, deltorphin II (DLT: Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH 2 ) and Leu-enkephalin (ENK: Tyr-Gly-Gly-Phe-Leu), containing Dmp or Dmt at position 1. MATERIALS AND METHODSPeptide Synthesis Peptides were generated by solid phase synthesis using a DIC/HOBt-mediated Fmoc strategy, as previously described.15) Fmoc-Dmp or Boc-Dmt used was prepared by the method reported previously. 13,17) For the synthesis of DLT analogues (1, 2), an N-terminal Dmp residue was incorporated using Fmoc-Dmp racemate.17) Cleavage of the peptides from the resin was carried out by treatment with TFA-phenol (95 : 5) at room temperature for 1 h. The diastereoisomeric peptides (1, 2) were separated using medium-pressure HPLC, as described previously.18) The absolute configuration of the Dmp residue in 1 and 2 was determined by the analysis of the HCl hydrolysate of the peptides using chiral TLC plates (CH 3 CN : MeOH : H 2 Oϭ4 : 1 : 1). 17)Analytical HPLC (YMC-Pack ODS-AM-302 column, 150ϫ 4.6 mm) demonstrated that the purity of all peptides was Ͼ96%. All analogues reported here gave satisfactory FAB-MS and amino acid analytical data (Table 1).Receptor Binding Assay The opioid receptor binding assays were performed as described previously. In Vitro Bioactivity Assay The in vitro biological activities were evaluated using guinea pig ileum (GPI) and mouse vas deferens (MVD) tissues, as detailed previously.15) Isolated longitudinal muscle strips from Hartley strain guinea pig (250-300 g) and vas deferens from ddY strain mice (25-35 g) ...

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“…13,17) For the synthesis of DLT analogues (1, 2), an N-terminal Dmp residue was incorporated using Fmoc-Dmp racemate.…”

Section: Methodsmentioning

confidence: 99%

Section: Peptide Synthesismentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Sasaki

Ariizumi

et al. 2004

Biological & Pharmaceutical Bulletin

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“…It permits an examination of the topographical requirements for peptide bioactivities, [1][2][3] improved enzymatic stability, 4) constrained spatial conformation, 5) and the elicitation of novel biological properties. 6,7) In opioid peptides for example, the introduction of unnatural amino acids, such as 2Ј,6Ј-dimethyl-L-tyrosine (Dmt) as an analogue of tyrosine and 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) as a conformationally constrained phenylalanine analogue, play critical roles in the development of unique ligands for the investigation of structure-activity relationships of d-and m-opioid ligands.…”

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confidence: 99%

Enantioselective Synthesis of a Phenylalanine Library Containing Alkyl Groups on the Aromatic Moiety: Confirmation of Stereostructure by X-Ray Analysis

Tsuda

Minoura

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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19) During the synthesis, Z-configuration of acetamidoacrylate after Heck reaction and L-configuration of the final phenylalanine analogues were confirmed by X-ray analysis.According to the Chart 1, L-phenylalanine analogues were prepared. The starting materials, 2-iodotoluene (1a; Sigma- Six phenylalanine analogues containing 2-methyl-, 2,6-dimethyl-, 2-ethyl-6-methyl-, 2-isopropyl-6-methyl-, 2,4,6-trimethyl-, and 3,5-dimethyl-L-phenylalanine were synthesized enantioselectively through asymmetric hydrogenation of acetamidoacrylate derivatives. Enzymatic digestion and X-ray analysis supported the L-configuration of the phenylalanine derivatives obtained.

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Narcotic Analgesics

Aldrich

Vigil‐Cruz

2003

Burger's Medicinal Chemistry and Drug Discovery

147

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Narcotic analgesics such as morphine have been the mainstay for the treatment of severe pain, although these drugs are associated with serious adverse effects, most notably addiction liability and respiratory depression. Therefore there has been an intensive effort to find new therapeutic agents that retain the effectiveness of morphine, but do not have its undesired side effects. Compounds have been identified from a wide variety of chemical classes, from the rigid morphinan alkaloids to the flexible phenylpiperidines and the opioid peptides, which have affinity for opioid receptors. In recent years considerable effort has focused on identifying ligands, both agonists and antagonists, with affinity for delta (δ) and kappa (κ) opioid receptors as pharmacological tools and as potential therapeutic agents that would not have the side‐effect profile of morphine and other agonists that interact with mu (μ) opioid receptors. After the identification of the closely related opioid receptor‐like (ORL1) receptor and its endogenous ligand orphanin FQ/nociceptin, there has been considerable effort directed toward identifying agonists and antagonists for this receptor as well. This review discusses the structure‐activity relationships for each of the major classes of compounds that interact with the opioid receptors, along with ligands for the ORL1 receptors.

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Biological Properties of Opioid Peptides Replacing Tyr at Position 1 by 2,6-Dimethyl-Tyr.

Cited by 51 publications

References 0 publications

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

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

Enantioselective Synthesis of a Phenylalanine Library Containing Alkyl Groups on the Aromatic Moiety: Confirmation of Stereostructure by X-Ray Analysis

Narcotic Analgesics

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