G protein-coupled receptor 68 (GPR68) is originally discovered as a clinically related receptor in an ovarian cancer cell line.
GPR68 widely expresses in most cells and tissues, including the spleen, testes, small intestine, et al. Additionally, the most abundant area is in the brain, especially in the hippocampus.
GPR68 involves many biological processes, including pH homeostasis, tumor growth, and metastasis, inflammation. Besides, the receptor also functions as a mechanotransducer that senses shear stress in arteries.

In this article, we will introduce a selective positive allosteric modulator of GPR68, MS48107.

MS48107 is selective for GPR68 over the closely related proton GPCRs, neurotransmitter transporters, and hERG ion channels.
5-HT2B has a moderate binding affinity to MS48107 with a Ki value of 219 nM. At 5-HT2B receptors, MS48107 shows no agonist activity but displays weak antagonist activity with a Ki value of 310 nM, respectively.
MS48107 has agonist activity only at the melatonin receptor 1 (MT1) and MT2 receptors. This compound is a weak full agonist at the MT1 receptor (EC50=320 nM). Additionally, it exhibits weak partial agonist activity at the MT2 receptor (EC50=540 nM). At the same time, MS48107 displays low binding affinities to MT1 (5900 nM) and MT2 (1100 nM) receptors.

In Vivo Pharmacokinetic (PK) Properties of MS48107. A single intraperitoneal injection at the dose of 25 mg/kg leads to high exposure levels (above 10 μM) in both plasma and brain at 0.5 h in mice. Additionally, The high compound exposure levels in both plasma and brain are maintained for 2 h. These results show that MS48107 is bioavailable and can readily cross the BBB in mice. Furthermore, there exhibit no clinical signs in test mice. Taken together, Compound MS48107 is a valuable chemical tool for investigating the biological function of GPR68 in vivo.

In conclusion, MS48107 is a promising GPR68 PAM and acts as a chemical tool for investigating GPR68 function in vitro and in vivo.


Xufen Yu, et al. J Med Chem. 2019 Aug 22;62(16):7557-7574.