Atrial natriuretic peptide receptor modulators: effects of disubstituted quinazolines on receptor binding and in vitro biological activity.
Prazosin (25 microM) was found to increase 125I-labeled rat atrial natriuretic peptide ([125I]rANP) receptor binding by 50% (SC50) in bovine adrenal zona glomerulosa membranes. A series of 2,4-disubstituted quinazolines was prepared in order to identify more potent analogues for additional in vitro testing. Compound 7 (N-[3-[[2-(diethyl-amino)-4-quinazolinyl]amino]propyl] guanidine dinitrate) from this series (3 microM) significantly decreased the EC50 for rANP-mediated inhibition of ACTH-stimulated aldosterone synthesis in rat adrenal glomerulosa cells. At a higher concentration (20 microM), compound 7 had no effect on particulate guanylate cyclase from rabbit glomeruli in either the presence or absence of rANP.
Yu
M J
MJ
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
McCowan
J R
JR
Steinberg
M I
MI
Wiest
S A
SA
Wyss
V L
VL
Horng
J S
JS
D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000450:Aldosterone / Q000096:biosynthesis; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D004789:Enzyme Activation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism; D007678:Kidney Glomerulus / Q000201:enzymology; D008297:Male; D015394:Molecular Structure; D011224:Prazosin / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017461:Receptors, Atrial Natriuretic Factor; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D015384:Zona Glomerulosa / Q000187:drug effects / Q000378:metabolism
D011799:Quinazolines; D011956:Receptors, Cell Surface; D000450:Aldosterone; D009320:Atrial Natriuretic Factor; D000324:Adrenocorticotropic Hormone; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; D011224:Prazosin