Ovarian-cancer G protein-coupled receptor 1 (OGR1, alias GPR68, coupled to Gq proteins) is a proton-sensing GPCR initially cloned from ovarian cancer cells. This GPCR is responsive to pH changes in the extracellular extracellular matrix – at pH 7.8 there is no signaling activity, while at pH 6.8 the receptor is maximally activated. OGR1 is expressed in mesenchymal cells such as osteoblasts and vascular smooth muscle cells, and also in lymphocytes and neurons. The receptor has been implicated in the regulation of bone metabolism, inflammation, vascular biology and cancer cell adaptation to low extracellular pH. In addition, a homozygous defect in OGR1 leads to amelogenesis imperfecta in humans. The involvement of acidosis-activated OGR1 in pathophysiological processes calls for the development of OGR1 antagonists. We will report on the discovery of a series of small molecular weight OGR1 antagonists that was identified by screening fibroblasts expressing recombinant human OGR1, assessing calcium release from intracellular stores in response to a rapid extracellular pH shift from pH 7.6 to pH 6.8. A series of (2-hydroxybenzylidene)-hydrazides have been identified with examples that exhibit significant inhibitory potency against OGR1 and selectivity against GPR4, TDAG8, and other unrelated GPCRs thereby representing suitable tools to further elucidate the function and role of OGR1. A representative example, BA-39-PQ30, selectively inhibited OGR1 with an IC50 of 44 nM, and showed inhibitory activity in all cell systems tested where OGR1 is expressed. In TNF-treated synoviocytes, acidosis-induced release of IL8 was effectively inhibited by this compound.

Discovery of low molecular weight antagonists of the proton-sensing receptor OGR1

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