Pharmacological Profile and Molecular Modeling of Cyclic Opioid Analogues Incorporating Various Phenylalanine Derivatives
| Autor: | Alicja Kluczyk, Anna Adamska-Bartłomiejczyk, Anna Janecka, Piotr F. J. Lipiński, Justyna Piekielna-Ciesielska |
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| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Molecular model Stereochemistry medicine.drug_class Phenylalanine Peptide CHO Cells Peptides Cyclic 01 natural sciences Biochemistry Structure-Activity Relationship Cricetulus Opioid receptor Drug Discovery medicine Radioligand Animals Humans General Pharmacology Toxicology and Pharmaceutics Pharmacology chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Affinities Cyclic peptide 0104 chemical sciences Amino acid 010404 medicinal & biomolecular chemistry Opioid Receptors Opioid Molecular Medicine medicine.drug |
| Zdroj: | ChemMedChem. 15:1322-1329 |
| ISSN: | 1860-7187 1860-7179 |
| DOI: | 10.1002/cmdc.202000248 |
| Popis: | Peptide-based agonists of the μ opioid receptor (μOR) are promising therapeutic candidates for pain relief with reduced side effects compared to morphine. A deep understanding of μOR-ligand interactions is necessary for future design of peptide-based opioid analgesics. To explore the requirements of the μOR binding pocket, eight new analogues of our cyclic peptide Tyr-c[d-Lys-Phe-Phe-Asp]NH2 displaying high μOR affinity were synthesized, in which Phe in either the third or fourth position was replaced by various derivatives of this amino acid (β3 -Phe, homoPhe, β3 -homoPhe and PhGly). The aim of this research was to examine the structural effects of such modifications on the bioactivity, and both experimental and theoretical methods were used. The binding of the cyclic analogues to all three OR types (μ, δ, κ) was assessed by radioligand competitive binding assay, and their functional activity was determined in a calcium mobilization assay. In order to provide structural hypotheses explaining the obtained experimental affinities, the complexes of the cyclic peptides with μOR were subjected to molecular modeling. |
| Databáze: | OpenAIRE |
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