Single point D-substituted corticotropin-releasing factor analogs: effects on potency and physicochemical characteristics
| Autor: | Wylie Vale, R. Galyean, Jean Rivier, Charleen Miller, Catherine Rivier, Gayle Yamamoto, Antonio Miranda, A. G. Craig, Marvin R. Brown |
|---|---|
| Rok vydání: | 1993 |
| Předmět: |
Male
Agonist medicine.medical_specialty Epinephrine Corticotropin-Releasing Hormone medicine.drug_class Molecular Sequence Data Blood Pressure Peptide hormone Protein Structure Secondary Rats Sprague-Dawley Norepinephrine Structure-Activity Relationship Adrenocorticotropic Hormone Heart Rate In vivo Internal medicine Drug Discovery medicine Animals Potency Amino Acid Sequence chemistry.chemical_classification Sheep Circular Dichroism Antagonist Biological activity In vitro Rats Amino acid Endocrinology chemistry Molecular Medicine Peptides |
| Zdroj: | Journal of Medicinal Chemistry. 36:2851-2859 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00072a003 |
| Popis: | In an attempt to determine which conformational parameters are important for the biological activity of ovine corticotropin-releasing factor (oCRF), we have synthesized in significant amounts (50-200 mg) and characterized chemically, structurally (CD), and biologically, oCRF analogues with substitution of each amino acid by its corresponding D-isomer. Out of 37 of these analogues, three were found to be equipotent to, or twice as potent as, oCRF, 13 had potencies in the range from 10 to 60%, 17 had potencies ranging from 1 to 10%, and the four others had potencies less than 0.5%. None of the analogues antagonized oCRF-induced release of ACTH in vitro at concentrations > or = 1000 oCRF. Since antagonists to CRF action can be generated by deletion of the first 8-14 residues, a series of CRF antagonists which exhibit significantly higher in vitro and in vivo biological potency than [Met18,Lys23,Glu27,29,40,Ala32,41,-Leu33,3 6,38] h/rCRF, [alpha-helical-CRF9-41], is also described. [D-Phe12,Nle21,38,Arg36]h/rCRF, in particular, was found to be ca. 15 times more potent than alpha-helical-CRF9-41 in vitro. In the rat, however, this analogue was about as effective as alpha-helical-CRF9-41 in blocking CRF-induced decrease in mean arterial blood pressure and increase in heart rate. Its potency in blocking epinephrine release by CRF was not significantly different from that of alpha-helical-CRF9-41. In the adrenalectomized rat, [Lys36]alpha-helical-CRF(9-41) (1.7 mg/kg) blunted the effect of endogenous CRF over a 90-min period; by comparison, a similar dose of alpha-helical-CRF9-41 was effective for less than 1 h. |
| Databáze: | OpenAIRE |
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