| Bioactivity | TCN238 is an orally bioavailable mGlu4 receptor positive allosteric modulator (PAM) with an EC50 of 1 μM[1]. | ||||||||||||
| Invitro | 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]. | ||||||||||||
| Name | TCN238 | ||||||||||||
| CAS | 125404-04-8 | ||||||||||||
| Formula | C12H11N3 | ||||||||||||
| Molar Mass | 197.24 | ||||||||||||
| Appearance | Solid | ||||||||||||
| Transport | Room temperature in continental US; may vary elsewhere. | ||||||||||||
| Storage |
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| Reference | [1]. East SP, et al. An orally bioavailable positive allosteric modulator of the mGlu4 receptor with efficacy in an animal model of motor dysfunction. Bioorg Med Chem Lett. 2010 Aug 15;20(16):4901-5. [2]. Pershina EV, et al. Subacute activation of mGlu4 receptors causes the feedback inhibition of its gene expression in rat brain. Life Sci. 2016 May 15;153:50-4. |