In vulnerable atherosclerotic plaques, intraplaque hemorrhages (IPH) result in hemolysis of red blood cells and release of hemoglobin and free hemin. Hemin activates platelets and leads to thrombosis. Agonism of the inhibitory platelet receptor ACKR3 inhibits hemin-dependent platelet activation and thrombus formation.
View Article and Find Full Text PDFBackground: Platelet receptors ACKR3 and CXCR4 play a crucial role in a variety of cardiovascular diseases. Like most chemokine receptors, CXCR4 is a G protein coupled receptor that induces platelet activation. In contrast, the atypical chemokine receptor 3 (ACKR3) lacks the ability to activate heterotrimeric G proteins and its activation leads to platelet inhibition and attenuates thrombus formation.
View Article and Find Full Text PDFACKR3, an atypical chemokine receptor, has been associated with prothrombotic events and the development of cardiovascular events. We designed, synthesized, and evaluated a series of novel small molecule ACKR3 agonists. Extensive structure-activity relationship studies resulted in several promising agonists with potencies ranging from the low micromolar to nanomolar range, for example, (EC = 111 nM, = 95%) and (EC = 69 nM, = 82%) in the β-arrestin-recruitment assay.
View Article and Find Full Text PDFThe atypical chemokine receptor 3 (ACKR3), formerly known as CXC-chemokine receptor 7 (CXCR7), has been postulated to regulate platelet function and thrombus formation. Herein, we report the discovery and development of first-in-class ACKR3 agonists, which demonstrated superagonistic properties with values of up to 160% compared to the endogenous reference ligand CXCL12 in a β-arrestin recruitment assay. Initial in silico screening using an ACKR3 homology model identified two hits, (EC 19.
View Article and Find Full Text PDFThe super-conserved receptors expressed in the brain (SREB) constitute a family of orphan G protein-coupled receptors that include GPR27 (SREB1), GPR85 (SREB2) and GPR173 (SREB3). Their sequences are highly conserved in vertebrates, and they are almost exclusively expressed in the central nervous system. This family of receptors has attracted much attention due to their putative physiological functions and their potential as novel drug targets.
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