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1.
J Pept Sci ; 22(8): 545-51, 2016 Aug.
Article in English | MEDLINE | ID: mdl-27443980

ABSTRACT

The synthesis of new dermorphin analogues is described. The (R)-alanine or phenylalanine residues of natural dermorphin were substituted by the corresponding α-methyl-ß-azidoalanine or α-benzyl-ß-azido(1-piperidinyl)alanine residues. The potency and selectivity of the new analogues were evaluated by a competitive receptor binding assay in rat brain using [(3) H]DAMGO (a µ ligand) and [(3) H]DELT (a δ ligand). The most active analogue in this series, Tyr-(R)-Ala-(R)-α-benzyl-ß-azidoAla-Gly-Tyr-Pro-Ser-NH2 and its epimer were analysed by (1) H and (13) C NMR spectroscopy and restrained molecular dynamics simulations. The dominant conformation of the investigated peptides depended on the absolute configuration around C(α) in the α-benzyl-ß-azidoAla residue in position 3. The (R) configuration led to the formation of a type I ß-turn, whilst switching to the (S) configuration gave rise to an inverse ß-turn of type I', followed by the formation of a very short ß-sheet. The selectivity of Tyr-(R)-Ala-(R) and (S)-α-benzyl-ß-azidoAla-Gly-Tyr-Pro-Ser-NH2 was shown to be very similar; nevertheless, the two analogues exhibited different conformational preferences. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.


Subject(s)
Analgesics, Opioid/chemistry , Drug Design , Opioid Peptides/chemistry , Receptors, Opioid, delta/agonists , Receptors, Opioid, mu/agonists , Alanine/chemistry , Amino Acid Sequence , Amino Acid Substitution , Analgesics, Opioid/chemical synthesis , Analgesics, Opioid/pharmacology , Animals , Azides/chemistry , Binding Sites , Binding, Competitive , Brain Chemistry , Cell Membrane/chemistry , Cell Membrane/drug effects , Cell Membrane/metabolism , Ligands , Molecular Dynamics Simulation , Opioid Peptides/chemical synthesis , Opioid Peptides/pharmacology , Phenylalanine/chemistry , Piperidines/chemistry , Protein Binding , Protein Structure, Secondary , Rats , Rats, Wistar , Receptors, Opioid, delta/metabolism , Receptors, Opioid, mu/metabolism , Structure-Activity Relationship
2.
J Pept Sci ; 22(4): 222-7, 2016 Apr.
Article in English | MEDLINE | ID: mdl-27028206

ABSTRACT

In this study, proteinogenic amino acids residues of dimeric dermorphin pentapeptides were replaced by the corresponding ß(3)-homo-amino acids. The potency and selectivity of hybrid α/ß dimeric dermorphin pentapeptides were evaluated by competetive receptor binding assay in the rat brain using [3H]DAMGO (a µ ligand) and [3H]DELT (a δ ligand). Tha analog containing ß(3)-homo-Tyr in place of Tyr (Tyr-D-Ala-Phe-Gly-ß(3)-homo-Tyr-NH-)2 showed good µ receptor affinity and selectivity (IC50 = 0.302, IC50 ratio µ/δ = 68) and enzymatic stability in human plasma.


Subject(s)
Aminobutyrates/chemistry , Opioid Peptides/chemical synthesis , Tyrosine/analogs & derivatives , Tyrosine/chemistry , Animals , Binding, Competitive , Drug Stability , Humans , Inhibitory Concentration 50 , Male , Opioid Peptides/metabolism , Opioid Peptides/pharmacology , Protein Binding , Rats , Rats, Wistar , Receptors, Opioid/metabolism
3.
Chem Biol Drug Des ; 87(6): 824-32, 2016 06.
Article in English | MEDLINE | ID: mdl-26808639

ABSTRACT

This article describes new deltorphin I analogs in which phenylalanine residues were replaced by the corresponding (R) or (S)-α-benzyl-ß-azidoalanine, α-benzyl-ß-(1-pyrrolidinyl)alanine, α-benzyl-ß-(1-piperidinyl)alanine, and α-benzyl-ß-(4-morpholinyl)-alanine residues. The potency and selectivity of the new analogs were evaluated by a competitive receptor binding assay in the rat brain using [(3) H]DAMGO (a µ ligand) and [(3) H]DELT (a δ ligand). The affinity of analogs containing (R) or (S)-α-benzyl-ß-azidoalanine in position 3 to δ-receptors strongly depended on the chirality of the α,α-disubstituted residue. The conformational behavior of peptides modified with (R) or (S)-α-benzyl-ß-(1-piperidinyl)Ala, which displays the opposite selectivity, was analyzed by (1) H and (13) C NMR. The µ-selective Tyr-d-Ala-(R)-α-benzyl-ß-(1-piperidinyl)Ala-Asp-Val-Val-Gly-NH2 lacks the helical conformation observed in the δ-selective Tyr-d-Ala-(S)-α-benzyl-ß-(1-piperidinyl)Ala-Asp-Val-Val-Gly-NH2 . Our results support the proposal that differences between δ- and µ-selective opioid peptides are attributable to the presence or absence of a spatial overlap between the N-terminal message domain and the C-terminal address domain.


Subject(s)
Glycine/chemistry , Oligopeptides/chemistry , Animals , Glycine/genetics , Oligopeptides/genetics , Protein Structure, Secondary , Rats , Structure-Activity Relationship
4.
Peptides ; 66: 13-8, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25708417

ABSTRACT

Biphalin, a synthetic opioid octapeptide with a palindromic sequence has high analgesic activity. Biphalin displays a strong affinity for µ and δ-opioid receptors, and a significant to κ-receptor. The paper reports the synthesis of novel analogs of biphalin containing ß(3)-homo-amino acid residues at the 4,4' positions and a hydrazine or 1,2-phenylenediamine linker. The potency and selectivity of the peptides were evaluated by a competitive receptor-binding assay in rat brain homogenate using [(3)H]DAMGO (a µ ligand) and [(3)H]DELT (a δ ligand). Analogs with ß(3)-h-p-NO2Phe in positions 4 and 4' are the most active compounds. Selectivity depends on the degree of freedom between the two pharmacophore moieties. Analogs with a hydrazine linker show noticeable binding selectivity to µ receptors (IC50(µ)=0.72nM; IC50(δ)=4.66nM), while the peptides with a 1,2-phenylenediamine linker show slight δ selectivity (IC50(µ)=10.97nM; IC50(δ)=1.99nM). Tyr-d-Ala-Gly-ß(3)-h-p-NO2PheNHNH-ß(3)-h-p-NO2Phe (1) and (Tyr-d-Ala-Gly-ß(3)-h-p-NO2PheNH)2 (2) produced greater antinociceptive effect compared to morphine after i.t. administration.


Subject(s)
Amino Acids/chemistry , Enkephalins/chemistry , Enkephalins/therapeutic use , Analgesics, Opioid/chemical synthesis , Analgesics, Opioid/chemistry , Analgesics, Opioid/metabolism , Analgesics, Opioid/therapeutic use , Animals , Enkephalins/chemical synthesis , Enkephalins/metabolism , Male , Pain/drug therapy , Peptides/chemical synthesis , Peptides/chemistry , Peptides/metabolism , Peptides/therapeutic use , Protein Binding , Rats , Rats, Wistar , Receptors, Opioid, delta/metabolism
5.
J Pept Sci ; 21(2): 120-5, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25558014

ABSTRACT

New analogues of deltorphin I (DT I, Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2 ), with the D-Ala residue in position 2 replaced by α-methyl-ß-azido(amino, 1-pyrrolidinyl, 1-piperidinyl or 4-morpholinyl)alanine, were synthesized by a combination of solid-phase and solution methods. All ten new analogues were tested for receptor affinity and selectivity to µ- and δ-opioid receptors. The affinity of analogues containing (R) or (S)-α-methyl-ß-azidoalanine in position 2 to δ-receptors strongly depended on the chirality of the α,α-disubstituted residue. Peptide II, containing (S)-α-methyl-ß-azidoalanine in position 2, displayed excellent δ-receptor selectivity with its δ-receptor affinity being only three times lower than that of DT I.


Subject(s)
Amino Acids/chemistry , Oligopeptides/chemistry , Oligopeptides/pharmacology , Receptors, Opioid, delta/agonists , Receptors, Opioid, mu/agonists , Animals , Ligands , Male , Models, Molecular , Molecular Structure , Rats , Rats, Wistar , Structure-Activity Relationship
6.
Chem Biol Drug Des ; 84(2): 199-205, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24674466

ABSTRACT

Biphalin, a synthetic opioid peptide with a broad affinity for all opioid receptors (δ, µ, and κ) and high antinociceptive activity, has been under extensive study as a potential analgesic drug. This study presents the synthesis and biological properties of four new analogues of biphalin containing amphiphilic α-alkylserines in position 2 and 2'. The incorporation of bulky α,α-disubstituted amino acids in the peptide chain using standard peptide chemistry is often unsuccessful. We synthesized depsipeptides, and then, the desired peptides were obtained by internal O,N-migration of the acyl residue from the hydroxyl to the amino group under mild basic conditions. The potency and selectivity of the new analogues were evaluated by a competitive receptor-binding assay in the rat brain using [(3)H]DAMGO (a µ ligand) and [(3)H]DELT (a δ ligand). Their binding affinity is strongly dependent on the chirality of α-alkylserine, as analogues containing (R)-α-alkylserines displayed higher µ receptor affinity and selectivity than those incorporating the (S)-isomers.


Subject(s)
Analgesics/chemistry , Analgesics/pharmacology , Enkephalins/chemistry , Enkephalins/pharmacology , Receptors, Opioid/metabolism , Animals , Brain/metabolism , Models, Molecular , Rats , Serine/chemistry , Serine/pharmacology
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