[3H]Metyrapol and 4-[131I]Iodometomidate Label Overlapping, but Not Identical, Binding Sites on Rat Adrenal Membranes

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• 作者：Michael L. Berger ; Friedrich Hammerschmidt ; Renzhe Qian ; Stefanie Hahner ; Andreas Schirbel ; Martina Stichelberger ; Roger Schibli ; Jie Yu ; Vladimir B. Arion ; Anna Woschek ; Elisabeth 脰hler ; Ilse M. Zolle
• 刊名：Molecular Pharmaceutics
• 出版年：2013
• 出版时间：March 4, 2013
• 年：2013
• 卷：10
• 期：3
• 页码：1119-1130
• 全文大小：474K
• 年卷期：v.10,no.3(March 4, 2013)
• ISSN：1543-8392

文摘

Metyrapone, metyrapol, and etomidate are competitive inhibitors of 11-deoxycorticosterone hydroxylation by 11尾-hydroxylase. [³H]Metyrapol and 4-[¹³¹I]iodometomidate bind with high affinity to membranes prepared from bovine and rat adrenals. Here we report inhibitory potencies of several compounds structurally related to one or both of these adrenostatic drugs, against the binding of both radioligands to rat adrenal membranes. While derivatives of etomidate inhibited the binding of both radioligands with similar potencies, derivatives of metyrapone inhibited the binding of 4-[¹³¹I]iodometomidate about 10 times weaker than the binding of [³H]metyrapol. By X-ray structure analysis the absolute configuration of (+)-1-(2-fluorophenyl)-2-methyl-2-(pyridin-3-yl)-1-propanol [(+)-11, a derivative of metyrapol] was established as (R). We introduce 1-(2-fluorophenyl)-2-methyl-2-(pyridin-3-yl)-1-propanone (9; K_i = 6 nM), 2-(1-imidazolyl)-2-methyl-1-phenyl-1-propanone (13; 2 nM), and (R)-(+)-[1-(4-iodophenyl)ethyl]-1H-imidazole (34; 4 nM) as new high affinity ligands for the metyrapol binding site on 11尾-hydroxylase and discuss our results in relation to a proposed active site model of 11尾-hydroxylase.

Keywords:

11尾-hydroxylase; metyrapone; [³H]metyrapol; etomidate; radioligand binding; rat adrenals