Conformationally constrained deltorphin analogs with 2-aminotetralin-2-carboxylic acid in position 3
| Autor: | Patricia Verheyden, Zsuzsa Darula, Anna Borsodi, Zsolt Böcskey, Antal Péter, H. Jaspers, Géza Tóth, Zoltán Tóth, Dirk Tourwé, Ferenc Fülöp |
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| Rok vydání: | 1997 |
| Předmět: |
Male
Magnetic Resonance Spectroscopy Stereochemistry Protein Conformation Deltorphin I Guinea Pigs Peptide Binding Competitive δ-opioid receptor chemistry.chemical_compound Mice Stereospecificity Vas Deferens Ileum Receptors Opioid delta Drug Discovery Peptide synthesis Animals Opioid peptide chemistry.chemical_classification Ligand binding assay Brain Rats Analgesics Opioid chemistry Opioid Peptides Deltorphin Molecular Medicine Oligopeptides Muscle Contraction Protein Binding |
| Zdroj: | Journal of medicinal chemistry. 40(6) |
| ISSN: | 0022-2623 |
| Popis: | Two approaches to the design of very active and highly selective delta opioid peptides were used to obtain new deltorpin analogs with altered hydrophobic and stereoelectronic properties. Deltorphin I and II analogs were synthesized involving the substitution of Ile instead of Val at positions 5 and 6 in the address domain and 2-aminotetralin-2-carboxylic acid (Atc) instead of Phe in the message domain. The peptides were agonists in the subnanomolar range in the MVD assay and in the micromolar or higher range in the GPI assay, showing a very high selectivity for delta receptors. A very similar trend could be observed in radioreceptor binding assays in which selective tritiated opioid ligands were used. (R)- and (S)-Atc-deltoriphins exhibited similar Ki values in the binding assay, with almost complete loss of the stereospecificity of the binding. Conformational studies provided evidence for the little disturbance of the backbone conformational equilibrium when Phe3 is replaced by (S)- or (R)-Atc. The use of the Atc constraint gives additional evidence that, during its interaction with the delta receptor, the side chain of residue 3 adopts the trans conformation at chi 1. |
| Databáze: | OpenAIRE |
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