Pharmacological differences between rat and human endothelin B receptors.
Cloned rat and human endothelin-B receptors (ETBR) were utilized to determine if there are significant pharmacological differences between highly homologous ETBR from different species. Recombinant rat and human ETBR were expressed in CHO-K1 cells, and radioligand binding studies were carried out with [125I]-ET-3 to determine the affinities of various ET receptor agonists and antagonists for rat and human ETBR. These receptors had similar affinities for a number of ETBR agonists (ET-1, ET-3, S6C, BQ 3020) and antagonists (Ro 47-0203, PD 142893). However, several peptide (PD 147452, PD 151583, BQ 788) and non-peptide (PD 156707, SB 209670) antagonists had different affinities for rat and human ETBR, with differences in Ki values between species ranging from 4.1- to 53.4-fold. The ETBR-selective agonist IRL 1620 also had a 5.7-fold higher affinity for rat ETBR than human ETBR. Thus despite their high degree of homology, rat and human ETBR show significant pharmacological differences with respect to both antagonist and agonist binding.
Reynolds
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EE
Department of Cardiovascular Therapeutics, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Hwang
O
O
Flynn
M A
MA
Welch
K M
KM
Cody
W L
WL
Steinbaugh
B
B
He
J X
JX
Chung
F Z
FZ
Doherty
A M
AM
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D011869:Radioligand Assay; D051381:Rats; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000819:agonists / Q000378:metabolism*; D011994:Recombinant Proteins; D013045:Species Specificity
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D011994:Recombinant Proteins