3 research outputs found
Overview of Metabolism and Bioavailability Enhancement of Polyphenols
A proper
diet is one of major factors contributing to good health
and is directly related to general condition of the organism. Phenolic
compounds are abundant in foods and beverages (fresh and processed
fruits and vegetables, leguminous plants, cereals, herbs, spices,
tea, coffee, wine, beer) and their pleiotropic biological activities
result in numerous health beneficial effects. On the other hand, high
reactivity and very large diversity in terms of structure and molecular
weight renders polyphenols one of the most difficult groups of compounds
to investigate, as evidenced by ambiguous and sometimes contradictory
results of many studies. Furthermore, phenolics undergo metabolic
transformations, which significantly change their biological activities.
Here, we discuss some aspects of metabolism and absorption of phenolic
compounds. On the basis of information reported in the literature
as well as in summaries of clinical trials and patent applications,
we also give an overview of strategies for enhancing their bioavailability
Pharmacological Characterization of μ-Opioid Receptor Agonists with Biased G Protein or β-Arrestin Signaling, and Computational Study of Conformational Changes during Receptor Activation
In recent years, G protein vs. β-arrestin biased agonism at opioid receptors has been proposed as an opportunity to produce antinociception with reduced adverse effects. However, at present this approach is highly debated, a reason why more information about biased ligands is required. While the practical relevance of bias in the case of µ-opioid receptors (MOP) still needs to be validated, it remains important to understand the basis of this bias of MOP (and other GPCRs). Recently, we reported two cyclopeptides with high affinity for MOP, the G protein biased Dmt-c[d-Lys-Phe-pCF3-Phe-Asp]NH2 (F-81), and the β-arrestin 2 biased Dmt-c[d-Lys-Phe-Asp]NH2 (C-33), as determined by calcium mobilization assay and bioluminescence resonance energy transfer-based assay. The biased character of F-81 and C-33 has been further analyzed in the [35S]GTPγS binding assay in human MOP-expressing cells, and the PathHunter enzyme complementation assay, used to measure β-arrestin 2 recruitment. To investigate the structural features of peptide-MOP complexes, we performed conformational analysis by NMR spectroscopy, molecular docking, and molecular dynamics simulation. These studies predicted that the two ligands form alternative complexes with MOP, engaging specific ligand–receptor contacts. This would induce different displays of the cytosolic side of the seven-helices bundle, in particular by stabilizing different angulations of helix 6, that could favor intracellular coupling to either G protein or β-arrestin
Synthesis of Mixed Opioid Affinity Cyclic Endomorphin‑2 Analogues with Fluorinated Phenylalanines
As
part of our continuing studies on the structure–activity relationships
of cyclic pentapeptides based on the structure of endomorphin-2 (EM-2),
we report here the synthesis and biological activities of a new series
of analogues of a general sequence Tyr/Dmt-c[d-Lys-Phe-Phe-Asp]NH<sub>2</sub> (where Dmt = 2′,6′-dimethyltyrosine), incorporating
fluorinated amino acids: 4-fluorophenylalanine (4-F-Phe), 2,4-difluorophenylalanine
(2,4-F-Phe), or 4-trifluoromethylphenylalanine (4-CF<sub>3</sub>-Phe)
instead of the Phe residue in position 3 or 4. Depending on the fluorinated
amino acid residue and its position in the sequence, analogues were
mixed, high affinity MOP/KOP receptor agonists, MOP/DOP/KOP agonists,
or selective KOP agonists. The <i>in vitro</i> potencies
and efficacies of all novel analogues were assessed in calcium mobilization
assay. The most potent analogues, Dmt-c[d-Lys-Phe-4-F-Phe-Asp]NH<sub>2</sub> and Dmt-c[d-Lys-Phe-2,4-F-Phe-Asp]NH<sub>2</sub>, were tested <i>in vivo</i> in the mouse hot-plate test.
They produced strong antinociceptive effect not only after intracerebroventricular
but also after intraperitoneal injection, indicating that they were
able to cross the blood–brain barrier