The C3a receptor antagonist SB 290157 has agonist activity.
The anaphylatoxin C3a is an important immune regulator with a number of distinct functions in both innate and adaptive immunity. Many of these roles have been ascribed to C3a based on studies in mice genetically modified to lack its precursor, C3, or its receptor, C3aR. However, other presumed functions of C3a are based on results obtained with a recently described small molecule ligand of C3aR, SB 290157. Although this compound was originally described as an antagonist and appears to act as such in some systems, it has recently been shown to have effects that cannot be explained by simple antagonism of C3aR. In the current study, SB 290157 is shown to have full agonist activity on C3aR in a variety of cell systems, including a calcium mobilization assay in transfected RBL cells, a beta-lactamase assay in CHO-NFAT-bla-Galpha(16) cells and an enzyme-release assay in differentiated U-937 cells. On the other hand, the compound lacks agonist activity in guinea pig platelets, cells known to express C3aR at very low levels. SB 290157 agonism of C3aR is consistent with recent discrepant data obtained using this molecule. These results caution against attributing novel roles to C3a based on data obtained with SB 290157 and highlight a continuing need for the identification of true small molecule C3aR antagonists.
Mathieu
Marie-Claude
MC
Department of Biochemistry and Molecular Biology, Merck Frosst Center for Therapeutic Research, Kirkland, Quebec, Canada H9H 3L1.
Sawyer
Nicole
N
Greig
Gillian M
GM
Hamel
Martine
M
Kargman
Stacia
S
Ducharme
Yves
Y
Lau
Cheuk K
CK
Friesen
Richard W
RW
O'Neill
Gary P
GP
Gervais
Francois G
FG
Therien
Alex G
AG
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001667:Binding, Competitive; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D015926:Complement C3a; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008252:Macaca fascicularis; D008565:Membrane Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; D051381:Rats; D011951:Receptors, Complement / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; D014162:Transfection; D020298:U937 Cells; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism
D001559:Benzhydryl Compounds; D008565:Membrane Proteins; D011951:Receptors, Complement; C431907:SB 290157; C085567:complement C3a receptor; D015926:Complement C3a; D001120:Arginine; D001618:beta-Lactamases; D002118:Calcium