Highly potent side chain-main chain cyclized dermorphin-deltorphin analogues: An integrated approach including synthesis, bioassays, NMR spectroscopy and molecular modelling
| Autor: | Nga N. Chung, Annika B. Malmberg, Arno F. Spatola, Thomas F. Burks, Qin Zhu, Murray Goodman, Seonggu Ro, Tony L. Yaksh, Krzysztof Darlak, Peter W. Schiller, Chang‐Woo Lee |
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| Rok vydání: | 1995 |
| Předmět: |
Male
Models Molecular Magnetic Resonance Spectroscopy Stereochemistry Guinea Pigs Receptors Opioid mu Peptide Phenylalanine In Vitro Techniques Biochemistry Mice Structure-Activity Relationship chemistry.chemical_compound Structural Biology Receptors Opioid delta Drug Discovery Antinociceptive Agents Side chain Animals Amino Acid Sequence Molecular Biology Pharmacology chemistry.chemical_classification Analgesics Molecular Structure Organic Chemistry General Medicine Nuclear magnetic resonance spectroscopy Dermorphin Rats Opioid Peptides chemistry Deltorphin Lactam Molecular Medicine Biological Assay Oligopeptides |
| Zdroj: | Journal of Peptide Science. 1:157-174 |
| ISSN: | 1099-1387 1075-2617 |
| DOI: | 10.1002/psc.310010303 |
| Popis: | Our continuing efforts to study structure-activity relationships of peptide opioids have resulted in the synthesis of a series of cyclic opioids related to dermorphins and deltorphins. The biological activities of the compounds have been determined and the conformational analyses carried out using 1H-NMR spectroscopy and molecular modelling. The three compounds in the series Tyr-c[D-Orn-Phe-Ala], Tyr-c[D-Lys-Phe-Ala], and Tyr-c[A2bu-Phe-Ala-Leu] are cyclized via a lactam bridge from the side-chain of the residue at the second position with the carboxyl terminus of each compound. The molecules incorporate 12-, 13- and 14-membered rings, respectively. They include a phenylalanine at the third position which is a distinguishing characteristic of dermorphins and deltorphins. The guinea pig ileum and mouse vas deferens assays show that the compounds are highly active at both mu- and delta-opioid receptors. The compounds are all highly effective antinociceptive agents as measured by the intrathecal rat hot plate test. Conformational analyses of the molecules indicate that they can adopt topochemical arrays required for bioactivity at both mu- and delta-receptors which explains their high activity in both guinea pig ileum and mouse vas deferens in vitro assays. The results support our models for mu- and delta-receptor activity for constrained peptide opioids. |
| Databáze: | OpenAIRE |
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