Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Dicarba analogues of the cyclic enkephalin peptides H-Tyr-c[D-Cys-Gly-Phe-D(or L)-Cys]NH(2) retain high opioid activity.

ABSTRACT: Dicarba analogues of the cyclic opioid peptides H-Tyr-c[d-Cys-Gly-Phe-d(or l)-Cys]NH2 were synthesized on solid phase by substituting allylglycines for the cysteines and cyclization by ring-closing metathesis between the side chains of the allylglycine residues. Mixtures of cis and trans isomers of the resulting olefinic peptides were obtained, and catalytic hydrogenation yielded the saturated -CH2-CH2- bridged peptides. The dicarba analogues retained high mu and delta agonist potencies. Remarkably, the trans isomer of H-Tyr-c[d-Allylgly-Gly-Phe-l-Allylgly]NH2 was a mu agonist/delta agonist with subnanomolar potency at both receptors.

SUBMITTER: Berezowska I

PROVIDER: S-EPMC2596712 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Dicarba analogues of the cyclic enkephalin peptides H-Tyr-c[D-Cys-Gly-Phe-D(or L)-Cys]NH(2) retain high opioid activity.

Berezowska Irena I Chung Nga N NN Lemieux Carole C Wilkes Brian C BC Schiller Peter W PW

Journal of medicinal chemistry 20070222 6

Dicarba analogues of the cyclic opioid peptides H-Tyr-c[d-Cys-Gly-Phe-d(or l)-Cys]NH2 were synthesized on solid phase by substituting allylglycines for the cysteines and cyclization by ring-closing metathesis between the side chains of the allylglycine residues. Mixtures of cis and trans isomers of the resulting olefinic peptides were obtained, and catalytic hydrogenation yielded the saturated -CH2-CH2- bridged peptides. The dicarba analogues retained high mu and delta agonist potencies. Remarka ...[more]

PMID: 17315860

Similar Datasets

Synthesis of stable and potent delta/mu opioid peptides: analogues of H-Tyr-c[D-Cys-Gly-Phe-D-Cys]-OH by ring-closing metathesis.

Project description:Ring-closing metathesis has emerged as a powerful tool in organic synthesis for generating cyclic structures via C-C double bond formation. Recently, it has been successfully used in peptide chemistry for obtaining cyclic molecules bridged through an olefin unit in place of the usual disulfide bond. Here, we describe this approach for obtaining cyclic olefin bridged analogues of H-Tyr-c[D-Cys-Gly-Phe-Cys]-OH. The synthesis of the new ligands was performed using the second generation Grubbs' catalyst. The resulting cis-8 (cDADAE) and trans-9 (tDADAE) were fully characterized and tested at delta, mu, and kappa opioid receptors. Also the linear precursor 13 (lDADAE) and the hydrogenated derivative 11 (rDADAE) also were tested. All the cyclic products containing a olefinic bond are slightly selective but highly active and potent for the delta and mu opioid receptors. Activity toward the kappa opioid receptors was absent or very low.

| S-EPMC2274921 | biostudies-literature

Synthesis and Opioid Activity of Tyr1 -ψ[(Z)CF=CH]-Gly2 and Tyr1 -ψ[(S)/(R)-CF3 CH-NH]-Gly2 Leu-enkephalin Fluorinated Peptidomimetics.

Project description:We describe the design, synthesis, and opioid activity of fluoroalkene (Tyr1 -ψ[(Z)CF=CH]-Gly2 ) and trifluoroethylamine (Tyr1 -ψ[(S)/(R)-CF3 CH-NH]-Gly2 ) analogues of the endogenous opioid neuropeptide, Leu-enkephalin. The fluoroalkene peptidomimetic exhibited low nanomolar functional activity (5.0±2 nm and 60±15 nm for δ- and μ-opioid receptors, respectively) with a μ/δ-selectivity ratio that mimics that of the natural peptide. However, the trifluoroethylamine peptidomimetics, irrespective of stereochemistry, did not activate the opioid receptors, which suggest that bulky CF3 substituents are not tolerated at this position.

| S-EPMC5486982 | biostudies-literature

A cyclic carbo-isosteric penta-depsipeptide: cyclo(Phe(1)-d-Ala(2)-Gly(3)-Phe(4)-APO(5)).

Project description:The title compound, cyclo(Phe(1)-d-Ala(2)-Gly(3)-Phe(4)-APO(5)), C26H32N4O5, is the minor diastereoisomer of a cyclic penta-peptidomimetic analogue containing a novel 2-amino-propyl lactone (APO) motif, which displays the same number of atoms as the native amino acid glycine and has a methyl group in place of the carbonyl O atom. The crystal structure presented here allows the analysis of the secondary structure of this unprecedented cyclic carbo-isosteric depsipeptide. The conformation of the central ring is stabilized by an intra-molecular N-H⋯O hydrogen bond between the carbonyl O atom of the first residue (Phe(1)) and the amide group H atom of the fourth residue (Phe(4)). Based on the previously reported hydrogen bond and on the values of the torsion angles ϕ and ψ, the loop formed by the first, second, third and fourth residues (Phe(1), d-Ala(2), Gly(3) and Phe(4)) can be classified as a type II' β-turn. The loop around the new peptidomimetic motif, on the other hand, resembles an open γ-turn containing a weak N-H⋯O hydrogen bond between the carbonyl group O atom of the fourth residue (Phe(4)) and the amide unit H atom of the first residue (Phe(1)). In the crystal, the peptidomimetic mol-ecules are arranged in chains along the b-axis direction. Within such a chain, the mol-ecules of the structure are linked via N-H⋯O hydrogen bonds between the amide group H atom of the secondary residue (d-Ala(2)) and the carb-oxy unit O atom of the fourth residue (Phe(4)) in a neighboring mol-ecule. The newly formed methyl stereocentre of the APO peptidomimetic motif (APO(5)) was obtained as the minor diastereoisomer in a ring-closing reductive amination reaction and adopts an R configuration.

| S-EPMC4331906 | biostudies-literature

Long-lasting antinociceptive effects of a novel dynorphin analogue, Tyr-D-Ala-Phe-Leu-Arg psi (CH(2)NH) Arg-NH(2), in mice.

Project description:Tyr-D-Ala-Phe-Leu-Arg psi (CH(2)NH) Arg-NH(2) (SK-9709) is a dynorphin derivative in which the peptide bond was replaced with a psi (CH(2)NH) bond. In the present study, the antinociceptive effects of SK-9709 were determined in an acetic acid-induced writhing test and a hot-plate test. In the acetic acid-induced writhing test, significant antinociceptive effects were observed after subcutaneous (s.c.), intracerebroventricular (i.c.v.) and intrathecal (i.t.) injection of SK-9709, with maximal effects at 120, 30 and 15 min, respectively. The antinociceptive effects were dose-dependent and ED(50) values (range of 95% confidence limits) after s.c., i.c.v. and i.t. injection were 1.36 (0.61 - 3.02) micromol kg(-1), 2.11 (1.18 - 3.79) and 0.79 (0.61 - 1.03) nmol per mouse, respectively. The effects of SK-9709 (s.c., i.c.v. and i.t.) were reversed by the opioid receptor antagonist naloxone (1.36 micromol kg(-1), s.c.). The effects of SK-9709 (s.c.) were also reversed by the selective mu-opioid receptor antagonist beta-funaltrexamine (4.7 nmol per mouse, i.c.v.), and kappa-opioid receptor antagonist nor-binaltorphimine (4.9 nmol per mouse, i.t.). In the hot-plate test, the antinociceptive effect of SK-9709 (s.c., i.c.v. and i.t.) was also dose-dependent with the maximal peak effect at 120, 15 and 15 min similarly to the acetic acid-induced writhing test. The antinociceptive effects were dose-dependent and ED(50) values (range of 95% confidence limits) after s.c., i.c.v. and i.t. injection were 39.1 (5.4 - 283.0) micromol kg(-1), 6.5 (4.0 - 10.7) and 7.4 (5.0 - 11.0) nmol per mouse, respectively. These findings indicated that systemically administered SK-9709 produced long-lasting antinociceptive effects and these effects were mediated by both supra-spinal mu- and spinal kappa-opioid receptors.

| S-EPMC1572722 | biostudies-other

Radiolabeling of a cyclic RGD (cyclo Arg-Gly-Asp-d-Tyr-Lys) peptide using sodium hypochlorite as an oxidizing agent.

Project description:A simple and rapid nonradioactive iodide labeling/radiolabeling method for peptides, using an inexpensive oxidizing agent such as sodium hypochlorite and a cyclic peptide, cRGDyK (cyclo Arg-Gly-Asp-d-Tyr-Lys), was developed in this work. Labeling reaction was optimized by conducting experiments under variable ratios of the reagents, the reaction times, and the pH. The study demonstrated that radiolabeling of the cyclic peptide was fast and pH independent. Monoiodinated and di-iodinated cRGDyK were formed under all conditions and varied with the ratio of the reagents and the reaction time. Total percent of the iodinated cRGDyK (monoiodinated and di-iodinated cRGDyK) varied between 44 and 100 depending on the reaction conditions. Excess cyclic peptide over equal molar ratio of sodium iodide and sodium hypochlorite yielded in predominant amounts of monoiodinated cRGDyK, ie, >60% under 2:1:1 ratio and ~88% under 5:1:1 ratio of cRGDyK:sodium iodide:sodium hypochlorite.

| S-EPMC6085888 | biostudies-literature

A conserved Gly436-Trp-Leu-Ala-Gly-Leu-Phe-Tyr motif in hepatitis C virus glycoprotein E2 is a determinant of CD81 binding and viral entry.

Project description:The hepatitis C virus (HCV) glycoproteins E1 and E2 form a heterodimer that mediates CD81 receptor binding and viral entry. In this study, we used site-directed mutagenesis to examine the functional role of a conserved G436WLAGLFY motif of E2. The mutants could be placed into two groups based on the ability of mature virion-incorporated E1E2 to bind the large extracellular loop (LEL) of CD81 versus the ability to mediate cellular entry of pseudotyped retroviral particles. Group 1 comprised E2 mutants where LEL binding ability largely correlated with viral entry ability, with conservative and nonconservative substitutions (W437 L/A, L438A, L441V/F, and F442A) inhibiting both functions. These data suggest that Trp-437, Leu-438, Leu-441, and Phe-442 directly interact with the LEL. Group 2 comprised E2 glycoproteins with more conservative substitutions that lacked LEL binding but retained between 20% and 60% of wild-type viral entry competence. The viral entry competence displayed by group 2 mutants was explained by residual binding by the E2 receptor binding domain to cellular full-length CD81. A subset of mutants maintained LEL binding ability in the context of intracellular E1E2 forms, but this function was largely lost in virion-incorporated glycoproteins. These data suggest that the CD81 binding site undergoes a conformational transition during glycoprotein maturation through the secretory pathway. The G436P mutant was an outlier, retaining near-wild-type levels of CD81 binding but lacking significant viral entry ability. These findings indicate that the G436WLAGLFY motif of E2 functions in CD81 binding and in pre- or post-CD81-dependent stages of viral entry.

| S-EPMC1563787 | biostudies-literature

H-d-Phe-d-Pro-Gly methyl ester hydro-chloride monohydrate.

Project description:The conformation of the title tripeptide methyl ester hydro-chloride monohydrate, 1-[2-(methoxycarbonylmethylaminocarbonyl)pyrrolidin-1-ylcarbonyl]-2-phenylethanaminium chloride monohydrate, C(17)H(24)N(3)O(4) (+)·Cl(-)·H(2)O, is extended, but the structure cannot be classified as any typical secondary structure. Interactions through water molecules and chloride ions were formed, in addition to peptide-peptide hydrogen bonds, stabilizing the molecular packing. In comparison with the previous β-turn structure of the Phe-d-Pro-Gly analogue [Doi, Ichimiya & Asano (2007 ▶). Acta Cryst. E63, o4691], it was suggested that the difference between the chiralities of Phe and Pro residues of the title compound is important to induce the β-turn structure.

| S-EPMC2961031 | biostudies-literature

Characterizations and molecular docking mechanism of the interactions between peptide FDGDF (Phe-Asp-Gly-Asp-Phe) and SOD enzyme.

Project description:In this study, we investigated the antioxidant properties of dry-cured beef crude peptide (BPH) at different storage periods. The combination characteristics of different concentrations of Phe-Asp-Gly-Asp-Phe (FDGDF) and superoxide dismutase (SOD) at different temperatures were analyzed by ultraviolet-visible spectroscopy, fluorescence spectroscopy, and FT-IR spectroscopy, combined with the detection of a SOD activity detection box. It was found that FDGDF could improve the activity of SOD by changing its secondary structure. Bonds were formed at O32/O40/O52 using quantum chemical simulation calculations, and the Fukui index was higher than that of most atoms, indicating that these atoms were more likely to participate in the reaction. SPR biological force analysis showed that FDGDF and SOD were in a fast binding and dissociation mode. This study revealed the theoretical basis for studying the antioxidant mechanism of dry-cured beef and provided ideas for developing new dry-cured beef products.

| S-EPMC10826827 | biostudies-literature

N-terminal guanidinylation of TIPP (Tyr-Tic-Phe-Phe) peptides results in major changes of the opioid activity profile.

Project description:Derivatives of peptides of the TIPP (Tyr-Tic-Phe-Phe; Tic=1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) family containing a guanidino (Guan) function in place of the N-terminal amino group were synthesized in an effort to improve their blood-brain barrier permeability. Unexpectedly, N-terminal amidination significantly altered the in vitro opioid activity profiles. Guan-analogues of TIPP-related ? opioid antagonists showed ? partial agonist or mixed ? partial agonist/? partial agonist activity. Guanidinylation of the mixed ? agonist/? antagonists H-Dmt-Tic-Phe-Phe-NH2 (DIPP-NH2) and H-Dmt-Tic?[CH2NH]Phe-Phe-NH2 (DIPP-NH2[?]) converted them to mixed ? agonist/? agonists. A docking study revealed distinct positioning of DIPP-NH2 and Guan-DIPP-NH2 in the ? receptor binding site. Lys(3)-analogues of DIPP-NH2 and DIPP-NH2[?] (guanidinylated or non-guanidinylated) turned out to be mixed ?/? agonists with ? antagonist-, ? partial agonist- or ? full agonist activity. Compounds with some of the observed mixed opioid activity profiles have therapeutic potential as analgesics with reduced side effects or for treatment of cocaine addiction.

| S-EPMC3776131 | biostudies-literature

Chemical scale studies of the Phe-Pro conserved motif in the cys loop of Cys loop receptors.

Project description:The functions of two conserved residues, Phe(135) and Pro(136), located at the apex of the Cys loop of the nicotinic acetylcholine receptor are investigated. Both residues were substituted with natural and unnatural amino acids, focusing on the role of aromaticity at Phe(135), backbone conformation at Pro(136), side chain polarity and volume, and the specific interaction between the aromatic side chain and the proline. NMR spectroscopy studies of model peptides containing proline and unnatural proline analogues following a Phe show a consistent increase in the population of the cis conformer relative to peptides lacking the Phe. In the receptor, a strong interaction between the Phe and Pro residues is evident, as is a strong preference for aromaticity and hydrophobicity at the Phe site. A similar influence of hydrophobicity is observed at the proline site. In addition, across a simple homologous series of proline analogues, the results reveal a correlation between receptor function and cis bias at the proline backbone. This could suggest a significant role for the cis proline conformer at this site in receptor function.

| S-EPMC2838319 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data