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1.
Wound Repair Regen ; 28(2): 177-184, 2020 03.
Article in English | MEDLINE | ID: mdl-31667902

ABSTRACT

The purpose of this study was to investigate the effect of the peptide analgesic hybrid compounds: AWL3106 analog of dermorphin and substance P (7-11), and biphalin enkephalin analog on wound healing in streptozotocin-induced diabetic rats. The diabetes was induced in 6-7 week-old male Wistar rats by intraperitoneal injection of streptozotocin. After 70 days, the wounds were created on the back of the rats and then, once a day for 21 days, the dressing containing lanolin ointment, 10% of keratin scaffolds, and 1 mM of AWL3106 or biphalin was applied. The wounds histology were analyzed by hematoxylin and eosin staining. The orientation and organization of collagen was analyzed by Masson's trichome staining. The number of macrophages, blood vessels, and fibroblasts were visualized by CD68, CD34, and vimentin immunoreactivity, respectively. Our results demonstrated that the wound area of AWL3106- and biphalin-treated groups was greatly reduced (up to 47% on the 7 day) in comparison with untreated diabetic groups. The immunohistochemical staining of macrophages demonstrated that AWL3106 and biphalin accelerated inflammatory progression and subsequently decreased persistent inflammation. The histological analysis showed that the structure of tissue in the groups under the study was very similar to the one of wound tissue in N-DM group. The H&E and Masson's trichome staining demonstrated that the orientation and organization of collagen as well as the number and shape of blood vessels were better in 3106- and BIF-treated group than in DM group. In conclusion, the obtained data suggested that our hybrid peptides enhanced wound healing, particularly by accelerating the inflammatory phase and promoted the wound closure.


Subject(s)
Analgesics/pharmacology , Diabetes Mellitus, Experimental , Enkephalins/pharmacology , Macrophages/drug effects , Neovascularization, Physiologic/drug effects , Opioid Peptides/pharmacology , Peptide Fragments/pharmacology , Substance P/pharmacology , Wound Healing/drug effects , Animals , Collagen/drug effects , Collagen/metabolism , Epidermal Cells/drug effects , Fibroblasts/drug effects , Male , Rats , Rats, Wistar
2.
ACS Med Chem Lett ; 8(1): 73-77, 2017 Jan 12.
Article in English | MEDLINE | ID: mdl-28105278

ABSTRACT

The area of multitarget compounds, joining two pharmacophores within one molecule, is a vivid field of research in medicinal chemistry. Not only pharmacophoric elements are essential for the design and activity of such compounds, but the type and length of linkers used to connect them are also crucial. In the present contribution, we describe compound 1 in which a typical opioid peptide sequence is combined with a fragment characteristic for neurokinin-1 receptor (NK1R) antagonists through a hydrazone bridge. The compound has a high affinity for µ- and δ-opioid receptors (IC50= 12.7 and 74.0 nM, respectively) and a weak affinity for the NK1R. Molecular modeling and structural considerations explain the observed activities. In in vivo test, intrathecal and intravenous administrations of 1 exhibited a strong analgesic effect, which indicates potential BBB penetration. This letter brings an exemplary application of the hydrazone linker for fast, facile, and successful preparation of chimeric compounds.

3.
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
4.
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
5.
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
6.
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
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