title: Identification of a selective nonpeptide antagonist of the anaphylatoxin C3a receptor that demonstrates antiinflammatory activity in animal models.
abstract: The anaphylatoxin C3a is a potent chemotactic peptide and inflammatory mediator released during complement activation which binds to and activates a G-protein-coupled receptor. Molecular cloning of the C3aR has facilitated studies to identify nonpeptide antagonists of the C3aR. A chemical lead that selectively inhibited the C3aR in a high throughput screen was identified and chemically optimized. The resulting antagonist, N(2)-[(2,2-diphenylethoxy)acetyl]-L-arginine (SB 290157), functioned as a competitive antagonist of (125)I-C3a radioligand binding to rat basophilic leukemia (RBL)-2H3 cells expressing the human C3aR (RBL-C3aR), with an IC(50) of 200 nM. SB 290157 was a functional antagonist, blocking C3a-induced C3aR internalization in a concentration-dependent manner and C3a-induced Ca(2+) mobilization in RBL-C3aR cells and human neutrophils with IC(50)s of 27.7 and 28 nM, respectively. SB 290157 was selective for the C3aR in that it did not antagonize the C5aR or six other chemotactic G protein-coupled receptors. Functional antagonism was not solely limited to the human C3aR; SB 290157 also inhibited C3a-induced Ca(2+) mobilization of RBL-2H3 cells expressing the mouse and guinea pig C3aRS: It potently inhibited C3a-mediated ATP release from guinea pig platelets and inhibited C3a-induced potentiation of the contractile response to field stimulation of perfused rat caudal artery. Furthermore, in animal models, SB 290157, inhibited neutrophil recruitment in a guinea pig LPS-induced airway neutrophilia model and decreased paw edema in a rat adjuvant-induced arthritis model. This selective antagonist may be useful to define the physiological and pathophysiological roles of the C3aR.
authors.affiliation: Department of Molecular Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939, USA. bob_ames-1@sbphrd.com
authors.forename: R S
authors.initials: RS
authors.lastname: Ames
authors.forename: D
authors.initials: D
authors.lastname: Lee
authors.forename: J J
authors.initials: JJ
authors.lastname: Foley
authors.forename: A J
authors.initials: AJ
authors.lastname: Jurewicz
authors.forename: M A
authors.initials: MA
authors.lastname: Tornetta
authors.forename: W
authors.initials: W
authors.lastname: Bautsch
authors.forename: B
authors.initials: B
authors.lastname: Settmacher
authors.forename: A
authors.initials: A
authors.lastname: Klos
authors.forename: K F
authors.initials: KF
authors.lastname: Erhard
authors.forename: R D
authors.initials: RD
authors.lastname: Cousins
authors.forename: A C
authors.initials: AC
authors.lastname: Sulpizio
authors.forename: J P
authors.initials: JP
authors.lastname: Hieble
authors.forename: G
authors.initials: G
authors.lastname: McCafferty
authors.forename: K W
authors.initials: KW
authors.lastname: Ward
authors.forename: J L
authors.initials: JL
authors.lastname: Adams
authors.forename: W E
authors.initials: WE
authors.lastname: Bondinell
authors.forename: D C
authors.initials: DC
authors.lastname: Underwood
authors.forename: R R
authors.initials: RR
authors.lastname: Osborn
authors.forename: A M
authors.initials: AM
authors.lastname: Badger
authors.forename: H M
authors.initials: HM
authors.lastname: Sarau
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology; D001559:Benzhydryl Compounds / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive; D002460:Cell Line; D015926:Complement C3a / Q000378:metabolism*; D003169:Complement Inactivator Proteins / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D004487:Edema / Q000473:pathology / Q000517:prevention & control; D006168:Guinea Pigs; D006614:Hindlimb; D006801:Humans; D007274:Injections, Intraperitoneal; D007964:Leukocytosis / Q000276:immunology / Q000473:pathology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D020556:Neutrophil Infiltration / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D011951:Receptors, Complement / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001559:Benzhydryl Compounds; D003169:Complement Inactivator Proteins; D008565:Membrane Proteins; D011951:Receptors, Complement; C431907:SB 290157; C085567:complement C3a receptor; D015926:Complement C3a; D001120:Arginine