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

作者：Berger Michael L^*; Hammerschmidt Friedrich; Qian Renzhe; Hahner Stefanie; Schirbel Andreas; Stichelberger Martina; Schibli Roger; Yu Jie; Arion Vladimir B; Woschek Anna; Oehler Elisabeth; Zolle Ilse M

来源：Molecular Pharmaceutics, 2013, 10(3): 1119-1130.

DOI：10.1021/mp3006227

• 11 beta-hydroxylase
• metyrapone
• [H-3]metyrapol
• etomidate
• radioligand binding
• rat adrenals

Metyrapone, metyrapol, and etomidate are competitive inhibitors of 11-deoxycorticosterone hydroxylation by 11 beta-hydroxylase. [H-3]Metyrapol and 4- [I-131]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-[I-131]iodometomidate about 10 times weaker than the binding of [H-3]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 beta-hydroxylase and discuss our results in relation to a proposed active site model of 11 beta-hydroxylase.

• 出版日期2013-3