BRD5075 is a potent, specific activator / positive allosteric modulator (PAM) of GPR65, induces GPR65-dependent cAMP production with EC50 of 3.8 and 6.9 uM for WT GPR65 and GPR65 I231L respectively, regulates GPR65-dependent inflammatory cytokine and chemokine expression.
BRD5075 demonstrates the highest activity for hGPR65 and mGPR65 at 1.56 μM.
BRD5075 exhibits robust induction of cAMP activity and recruited G protein for the WT and variant hGPR65 as well as for the mouse ortholog.
BRD5075 is able to recruit G protein in cells expressing the variant hGPR65 I231L.
BRD5075 (5 uM, 20 uM) shows strong inhibitory effect of low pH on TNF secretion and further TNF suppression in MDDCs stimulated with lipopolysaccharide (LPS).
BRD5075 can potentiate GPR65 and the risk variant I231L to rebalance inflammatory responses.
GPR65 is a proton-activated heterotrimeric GTP-binding protein (G protein)–coupled receptor (GPCR) expressed primarily on myeloid and lymphoid immune cells that has been implicated through genetics in multiple autoimmune and inflammatory diseases.