[(3)H]metyrapol and 4-[(131)i]iodometomidate label overlapping, but not identical, binding sites on rat adrenal membranes.
Metyrapone, metyrapol, and etomidate are competitive inhibitors of 11-deoxycorticosterone hydroxylation by 11β-hydroxylase. [(3)H]Metyrapol and 4-[(131)I]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-[(131)I]iodometomidate about 10 times weaker than the binding of [(3)H]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; Ki = 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 11β-hydroxylase and discuss our results in relation to a proposed active site model of 11β-hydroxylase.
Center for Brain Research, Medical University of Vienna, Austria. michael.berger@meduniwien.ac.at
Michael L
ML
Berger
Friedrich
F
Hammerschmidt
Renzhe
R
Qian
Stefanie
S
Hahner
Andreas
A
Schirbel
Martina
M
Stichelberger
Roger
R
Schibli
Jie
J
Yu
Vladimir B
VB
Arion
Anna
A
Woschek
Elisabeth
E
Öhler
Ilse M
IM
Zolle
D000311:Adrenal Glands / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism*; D005045:Etomidate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D008797:Metyrapone / Q000737:chemistry* / Q000378:metabolism; D051381:Rats
C529450:iodophenyl metomidate; D005045:Etomidate; D008797:Metyrapone