, -Dimethylphenylalanine : A Useful Aromatic Amino Acid Surrogate for Tyr or Phe Residue in Opioid Peptides

Abstract

Two aromatic amino acids, Tyr1 and Phe3 or Phe4, are important structural elements in opioid peptides because they interact with opioid receptors. The usefulness of an artificial amino acid residue 2′,6′-dimethylphenylalanine (Dmp) was investigated as an aromatic amino acid surrogate for several opioid peptides, including enkephalin, dermorphin, deltorphin, endomorphin, dynorphin A, and nociceptin peptides. In most peptides, substitutions of Phe3 by a Dmp residue produced analogs with improved receptor-binding affinity and selectivity, while the same substitution of Phe4 induced markedly reduced receptor affinity and selectivity. Interestingly, replacement of Tyr1 by Dmp produced analogs with unexpectedly high affinity or produced only a slight drop in receptor affinity and bioactivity for most peptides. Thus, Dmp is also a useful surrogate for the N-terminal Tyr residue in opioid peptides despite the lack of a phenolic hydroxyl group, which is considered necessary for opioid activity. The Dmp1-substituted analogs are superior to 2′,6′-dimethyltyrosine (Dmt)1-substituted analogs for high receptor selectivity since the latter generally have poor receptor selectivity. Thus, Dmp is very useful as an aromatic amino acid surrogate in opioid peptides and may be useful for developing other novel peptide mimetics with high receptor specificity.

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

“…124–127 To fully understand the antioxidant mechanisms of Dmt-containing peptides, it will be important to compare the effects of SS peptides with analogous compounds containing dimethylphenylalanine in place of Dmt. 128 …”

“…Examples of such peptides include a series of compounds known as Szeto–Schiller (SS) peptides, which are designed to deliver dimethyltyrosine (Dmt) as an antioxidant motif to mitochondria. − However, Dmt as a phenolic compound is not expected to exhibit significant direct scavenging ability toward the superoxide radical anion or hydroperoxides. Thus, other mechanisms of the protective activity of SS peptides may be in play, including their interaction with opioid receptors. − To fully understand the antioxidant mechanisms of Dmt-containing peptides, it will be important to compare the effects of SS peptides with analogous compounds containing dimethylphenylalanine in place of Dmt …”

“…124−127 To fully understand the antioxidant mechanisms of Dmt-containing peptides, it will be important to compare the effects of SS peptides with analogous compounds containing dimethylphenylalanine in place of Dmt. 128 To protect the peptides from enzymatic cleavage, the Disomer of arginine was incorporated. The structural requirements (the amino acid sequence, hydrophobicity, and a charge of the peptide) for efficient mitochondria-penetrating peptides (MPP, Chart 2) were subsequently studied.…”

The Role Of Amino Acid Arginine And Nitric Oxide System In Implementing Cardioprotective Effect Of Non-Opioid Analogue Of Leu-Enkephalin In Newborn Albino Rats After Intrauterine Hypoxia

“…The peptide Phe-D-Ala-Gly-Phe-Leu-Arg is a structural analogue of leu-enkephalin with three structural modifications: (1) the addition of the C-terminal amino acid Arg; (2) replacement of the amino acid Gly in the second position of the amino acid chain with amino acid D-Ala to increase the resistance of the peptide to the action of endopeptidases [6]; (3) replacement of the Nterminal amino acid Tyr with amino acid Phe. Since the N-terminal amino acid Tyr is crucial for the interaction of opioid peptides with specific receptors [3], the Phe-D-Ala-Gly-Phe-Leu-Arg peptide is incapable of binding to opioid receptors and was named a nonopioid analogue of leu-enkephalin (NALE).…”

“…NALE is characterized by cytoprotective and antioxidant effects in vitro [2]. This peptide has no affinity for opioid receptors due to the substitution of the N-terminal amino acid Tyr in the structure of leu-enkephalin for the amino acid Phe [3]. In this regard, the mechanisms of NALE effects remain uncertain.…”