TCN238

TCN238 is an orally bioavailable mGlu4 receptor positive allosteric modulator (PAM) with an EC₅₀ of 1 μM^[1]. IC50 & Target: EC50: 1 μM (human or rat mGlu4)^[1] In Vitro: In the rat mGlu4 PAM in vitro assay the EC₅₀ of TCN238 (Compound 11) is 1 μM which is comparable to the human assay. TCN238 is screened in rat and human mGlu5 assays, the IC₅₀ of 11 is >30 μM on human mGlu5and >10 μM on rat mGlu5. TCN238 is run in a receptor screening panel of 68 targets and no activity is observed at ≥50% at 10 μM for any of the receptors. In CaCo-2 cells, TCN238 is found to have good permeability with no apparent efflux issue^[1]. In Vivo: TCN238 is highly CNS penetrant with a concentration of 33.8 μM in the brain. The plasma protein binding in rats is measured as 90% bound. The metabolic stability of TCN238 is assessed in rat and human microsomes and found to be 62% and 83% hepatic blood flow. The limited stability translated into a high in vivo clearance in rats of 75 mL/min/kg and TCN238 has a moderate volume of distribution (2.7 L/kg) with a short mean residence time (0.6 h) when dosed at 2 mg/kg via intravenous injection. TCN238 is orally bioavailable and 30 min following administration of a30 mg/kg dose, the plasma concentration is found to be 11.6 μM^[1]. TCN 238 does not affect the performance of the learned task. However, the expression level of GRM4 in the hippocampus is reliable down-regulated five days after treatment with TCN 238. In addition, the expression level of GABRA1, encoding GABAA α-subunit is downregulated five days after the treatment in the frontal cortex^[2].