title: The C3a receptor antagonist SB 290157 has agonist activity.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Merck Frosst Center for Therapeutic Research, Kirkland, Quebec, Canada H9H 3L1.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Mathieu
authors.forename: Nicole
authors.initials: N
authors.lastname: Sawyer
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Greig
authors.forename: Martine
authors.initials: M
authors.lastname: Hamel
authors.forename: Stacia
authors.initials: S
authors.lastname: Kargman
authors.forename: Yves
authors.initials: Y
authors.lastname: Ducharme
authors.forename: Cheuk K
authors.initials: CK
authors.lastname: Lau
authors.forename: Richard W
authors.initials: RW
authors.lastname: Friesen
authors.forename: Gary P
authors.initials: GP
authors.lastname: O'Neill
authors.forename: Francois G
authors.initials: FG
authors.lastname: Gervais
authors.forename: Alex G
authors.initials: AG
authors.lastname: Therien
mesh_terms: 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
chemical_list: 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