Comparative pharmacology of recombinant rat AT1A, AT1B and human AT1 receptors expressed by transfected COS-M6 cells.
1. Currently available antagonists and agonists cannot distinguish between angiotensin AT1 receptor subtypes. 2. We synthesized a series of compounds selected on the basis of having the most diverse structural features with respect to losartan (DuP753), the prototype non-peptide AT1 receptor antagonist. Using a radioligand-receptor binding assay and membranes prepared from COS-M6 cells transfected with individual AT1 receptor subtypes, we determined whether any of these compounds could distinguish between the receptor subtypes. 3. The diversity of the structural features of this series of compounds was reflected by the wide range of affinities (pIC50 values) displayed towards competing with [125I]-Sar1Ile8 angiotensin II for binding to the AT1 receptors. 4. Direct comparisons of the pIC50 values of individual compounds for rat AT1A, AT1B and human AT1 receptors revealed only minor differences. 5. It is concluded that compounds based structurally on losartan are unlikely to distinguish between these receptors.
Balmforth
A J
AJ
Department of Cardiovascular Studies, University of Leeds, Middlesex.
Bryson
S E
SE
Aylett
A J
AJ
Warburton
P
P
Ball
S G
SG
Pun
K T
KT
Middlemiss
D
D
Drew
G M
GM
D000803:Angiotensin I / Q000031:analogs & derivatives / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology; D002460:Cell Line; D018076:DNA, Complementary / Q000302:isolation & purification / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan; D008566:Membranes / Q000378:metabolism; D010957:Plasmids; D016133:Polymerase Chain Reaction; D011869:Radioligand Assay; D051381:Rats; D011945:Receptors, Angiotensin / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D014162:Transfection
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D018076:DNA, Complementary; D007093:Imidazoles; D011945:Receptors, Angiotensin; D011994:Recombinant Proteins; D013777:Tetrazoles; D000803:Angiotensin I; D019808:Losartan