azd8797

Description: AZD8797 is a novel, selective, orally bioavailable and allosteric non-competitive modulator of the human CX3CR1 receptor; it antagonizes CX3CR1 and CXCR2 with Ki of 3.9 and 2800 nM, respectively. In a flow adhesion assay, AZD8797 antagonized the natural ligand, fractalkine (CX3CL1), in both human whole blood (hWB) and in a B-lymphocyte cell line with IC50 values of 300 and 6 nM respectively. AZD8797 also prevented G-protein activation in a (35)SGTPgammaS (guanosine 5'-gamma-thiotriphosphate) accumulation assay. In contrast, dynamic mass redistribution (DMR) experiments revealed a weak Galphai-dependent AZD8797 agonism. Additionally, AZD8797 positively modulated the CX3CL1 response at sub-micromolar concentrations in a beta-arrestin recruitment assay. In equilibrium saturation binding experiments, AZD8797 reduced the maximal binding of (125)I-CX3CL1 without affecting Kd. Kinetic experiments, determining the kon and koff of AZD8797, demonstrated that this was not an artefact of irreversible or insurmountable binding, thus a true non-competitive mechanism. Finally we show that both AZD8797 and GTPgammaS increase the rate with which CX3CL1 dissociates from CX3CR1 in a similar manner, indicating a connection between AZD8797 and the CX3CR1-bound G-protein. Collectively, these data show that AZD8797 is a non-competitive allosteric modulator of CX3CL1, binding CX3CR1 and effecting G-protein signalling and beta-arrestin recruitment in a biased way.

References:

1. CederbladL, et al. AZD8797 is an allosteric non-competitive modulator of thehuman CX3CR1 receptor. Biochem J. 2016 Mar 1; 473(5):641-9.

2. RidderstadWollberg A, et al. Pharmacological inhibition of the chemokine receptorCX3CR1 attenuates disease in a chronic-relapsing rat model for multiplesclerosis. Proc Natl Acad Sci U S A. 2014 Apr 8; 111(14):5409-14.

3. SofiaKarlstro?, et al. Substituted 7-amino-5-thio-thiazolo4, 5-dpyrimidinesas potent and selective antagonists of the fractalkine receptor(CX3CR1). J Med Chem. 2013 Apr 25; 56(8):3177-90.