SINGLE-POINT D-SUBSTITUTED CORTICOTROPIN-RELEASING FACTOR ANALOGS - EFFECTS ON POTENCY and PHYSICOCHEMICAL CHARACTERISTICS

SINGLE-POINT D-SUBSTITUTED CORTICOTROPIN-RELEASING FACTOR ANALOGS - EFFECTS ON POTENCY and PHYSICOCHEMICAL CHARACTERISTICS

Autor Rivier, J. Google Scholar
Rivier, C. Google Scholar
Galyean, R. Google Scholar
Miranda, A. Google Scholar
Miller, C. Google Scholar
Craig, A. G. Google Scholar
Yamamoto, G. Google Scholar
Brown, M. Google Scholar
Vale, W. Google Scholar
Instituição BACHEM INC
Universidade Federal de São Paulo (UNIFESP)
ZYMOGENET INC
UCSD
Resumo 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 greater-than-or-equal-to 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,-Leu33,36,38]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.
Idioma Inglês
Data de publicação 1993-10-01
Publicado em Journal of Medicinal Chemistry. Washington: Amer Chemical Soc, v. 36, n. 20, p. 2851-2859, 1993.
ISSN 0022-2623 (Sherpa/Romeo, fator de impacto)
Publicador Amer Chemical Soc
Extensão 2851-2859
Fonte http://dx.doi.org/10.1021/jm00072a003
Direito de acesso Acesso restrito
Tipo Artigo
Web of Science WOS:A1993MA32100003
Endereço permanente http://repositorio.unifesp.br/handle/11600/25355

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