TC-G-1008 (GPR39-C3) is a zinc receptor agonist with EC50 values of 0.4 nM for rat GPR39 and 0.8 nM for human GPR39.

rat GPR39
:0.4 nM, GPR139 (human):0.8 nM

TC-G-1008 demonstrates selectivity over a panel of kinases (IC50s>10 μM) and lacks significant binding affinity for the related ghrelin and neurotensin-1 receptors (IC50s>30 μM)[1]. GPR39-C3 acts as a positive allosteric modulator in HEK293-GPR39 cells, activating cAMP production (downstream of Gs), IP1 accumulation (downstream of Gq), SRF-RE-dependent transcription (downstream of G12/13), and β-arrestin recruitment, and induces dose- and time-dependent loss of response in cAMP production upon second challenge[2].

Rat and mouse plasma protein binding for TC-G-1008 is 99.3% and 99.1%, respectively. TC-G-1008 is the first potent GPR39 agonist (EC50s ≤ 1 nM for human and rat receptor) that is orally bioavailable in mice and significantly induces acute GLP-1 levels. Following single oral doses of 10, 30, and 100 mg/kg of aqueous suspensions in 0.5% methylcellulose/0.1% Tween 80, TC-G-1008 achieves maximal exposures of 1.4, 6.1, and 25.3 μM, respectively, between 1 and 1.5 hours[1].

HEK293-GPR39 cells are plated and cultured in poly-d-lysine-coated, white, 384-well plates (4000 cells/well) in the growth medium overnight at 37°C in the presence of 5% CO2. For pretreatment of the cells with GPR39 ligands (TCG-1008) or vehicle control (DMSO), the culture medium is removed and the cells are stimulated with GPR39 ligands in assay buffer for the indicated time at 37°C. Then, the compound solution is removed and washed twice with PBS containing 0.1% BSA. For measurement of intracellular cAMP, the cells are stimulated with drugs in stimulation buffer for 30 min at 37°C. The intracellular cAMP level is determined by using HTRF cAMP dynamic 2 kit[2] .

Mice: Mice are given single oral doses of 10, 30, and 100 mg/kg of TC-G-1008[1] .