Single point D-substituted corticotropin-releasing factor analogues: effects on potency and physicochemical characteristics.
Single point D-substituted corticotropin-releasing factor analogues: effects on potency and physicochemical characteristics.
复制标题
单点 D-取代促肾上腺皮质激素释放因子类似物：对效力和理化特性的影响。
DOI：
10.1021/jm00072a003
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发表时间：
1993
影响因子：
7.3
通讯作者：
Vale,W
中科院分区：
文献类型：
--
作者：
Rivier,J;Rivier,C;Galyean,R;Miranda,A;Miller,C;Craig,AG;Yamamoto,G;Brown,M;Vale,W
In an attempt to determine which conformational parameters are important for thebiological 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> 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,[a-helical-CRF^ i], is also described.[D-Phe12, Nle21-38, Arg36] h/rCRF, in particular, was found to be ca. 15 times more potent than a-helical-CRFg-u in vitro. In the rat, however, this analogue was about as effective as a-helical-CRF^ i inblocking CRF-induced decrease in mean arterial bloodpressure and increase in heart rate. Its potency in blocking epinephrine release by CRF was not significantly different from that of a-helical-CRF^ i. In the adrenalectomized rat,[Lys36] a-helical-CRF (9_4i,(1.7 mg/kg) blunted the effect of endogenous CRF over a 90-min period; by comparison, a similar dose of a-helical-CRFs-u was effective for less than 1 h.
