Toward the rational development of peptidomimetic analogs of the C-terminal endothelin hexapeptide: development of a theoretical model

التفاصيل البيبلوغرافية
العنوان: Toward the rational development of peptidomimetic analogs of the C-terminal endothelin hexapeptide: development of a theoretical model
المؤلفون: Marco Macchia, E. Menchini, Laura Giusti, Mahmoud Hamdan, R. P. Revoltella, Antonio Lucacchini, F. Romagnoli, Maria Rosa Mazzoni, Francesca Ceccarelli, Adriano Martinelli, Silvia Barontini, Paolo Rovero, Claudia Galoppini
المصدر: Il Farmaco. 53:545-556
بيانات النشر: Elsevier BV, 1998.
سنة النشر: 1998
مصطلحات موضوعية: Male, medicine.hormone, Protein Conformation, Peptidomimetic, Stereochemistry, Pharmaceutical Science, Peptide, Rats, Sprague-Dawley, Endothelins, Radioligand Assay, chemistry.chemical_compound, Cerebellum, Drug Discovery, medicine, Peptide synthesis, Animals, Amino Acid Sequence, Receptor, chemistry.chemical_classification, Receptors, Endothelin, Chemistry, Molecular Mimicry, Uterus, Biological activity, Receptor, Endothelin A, Ligand (biochemistry), Receptor, Endothelin B, Peptide Fragments, Rats, Models, Chemical, Drug Design, Female, Endothelin receptor
الوصف: In an early report on the structure-activity relationship of endothelin (ET) peptides, it was reported that the C-terminal hexapeptide ET(16-21), His-Leu-Asp-Ile-Ile-Trp, is the minimum ET fragment which maintains biological activity in some, but not all the tissues responding to ETs. Subsequently, other authors described a series of analogs of this peptide, in which the His 16 residue was replaced by non-natural amino acids, characterized by bulky aromatic side chains. Among them, two well-characterized non-selective ETA/ETB antagonists were PD 142893 and PD 145065; interest in these potent ET antagonists was, however, reduced by their peptidic structure which was likely to lead to undesirable properties such as poor bioavailability and short duration of action. On the basis of these premises, our previous studies led to the development of a peptidomimetic ligand of ET receptors (compound 3), based on the replacement of the His 16 residue of ET(16-21) with an (E)-N-(benzyloxy)iminoacyl moiety; compound 3 proved to possess a certain affinity for ET receptors, albeit lower than that shown by PD 142893 and PD 145065. We report here on ETA/ETB binding affinity of compounds 4-12, designed as a new series of ET(16-21) analogs. Compounds 4 and 5 were practically devoid of any affinity; derivatives 6-12 exhibited appreciable affinity indices for ETB receptors higher than that shown by 3, even if still lower than that obtained for PD 145065. This paper also describes the development of a pharmacophoric model able to explain the ET receptor binding properties of our hexapeptide analogs compared with those of PD 142893 and PD 145065 and IRL2500, recently reported as a potent ETB selective endothelin antagonist.
تدمد: 0014-827X
DOI: 10.1016/s0014-827x(98)00064-0
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::59ddbfab72aa07d528fb4a3e0d977263
https://doi.org/10.1016/s0014-827x(98)00064-0
Rights: CLOSED
رقم الانضمام: edsair.doi.dedup.....59ddbfab72aa07d528fb4a3e0d977263
قاعدة البيانات: OpenAIRE
الوصف
تدمد:0014827X
DOI:10.1016/s0014-827x(98)00064-0