TCN238 is an orally bioavailablemGlu4receptor positive allosteric modulator (PAM) with anEC₅₀of 1 μM^[1].

In the rat mGlu4 PAMin vitroassay the EC₅₀of TCN238 (Compound 11) is 1 μM which is comparable to the human assay. TCN238 is screened in rat and human mGlu5 assays, the IC₅₀of 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].

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 highin vivoclearance 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].

197.24

Solid

C₁₂H₁₁N₃

125404-04-8

Room temperature in continental US; may vary elsewhere.

DMSO : ≥ 150 mg/mL(760.49 mM)

*"≥" means soluble, but saturation unknown.

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