TCN 238

TCN238 is a positive allosteric mGlu4 receptor modulator with an EC50 of 1 μM.

In Vitro:In the rat mGlu4 PAM in vitro assay the EC50 of TCN238 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].

References:
[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.

Subacute activation of mGlu4 receptors causes the feedback inhibition of its gene expression in rat brain.[Pubmed:27055390]

Life Sci. 2016 May 15;153:50-4.

AIM: The present study aimed to understand the relationship between pharmacological activation of mGlu4 receptors and regulation of its gene in the hippocampus. MAIN METHODS: The expression level of the GRM4 gene, encoding mGluR4 receptors, was studied in the hippocampus and frontal cortex of rats after pharmacological activation of the receptor with positive allosteric modulator (E)-4-(2-Phenylethenyl)-2-pyrimidinamine (TCN 238). The drug was injected subcutaneously four times at a dose of 2mg/kg. The animals were previously trained with hippocampal-dependent task and after the treatment were tested for memory retrieval. The expression level of GRM4 was determined by qRT-PCR in control and experimental groups of animals one and five days post-treatment. KEY FINDINGS: We found that TCN 238 did not affect the performance of the learned task. However, the expression level of GRM4 in the hippocampus was reliable down-regulated five days after treatment with TCN 238. In addition, we showed that the expression level of GABRA1, encoding GABAA alpha-subunit was downregulated five days after the treatment in the frontal cortex. SIGNIFICANCE: Subacute pharmacological intervention in mGluR activity by the selective positive modulator TCN 238 has led to adaptive rearrangements of transcription processes in the hippocampus. Moreover, this regulation affected GABA system, confirming importance of the brain excitation-inhibition balance. Since the pharmacological influence on mGluR activity can be regarded as a promising tool aimed to correct brain dysfunction, the properties of mGluR modulators should be studied in more detail, including the level of gene transcription.

An orally bioavailable positive allosteric modulator of the mGlu4 receptor with efficacy in an animal model of motor dysfunction.[Pubmed:20638279]

Bioorg Med Chem Lett. 2010 Aug 15;20(16):4901-5.

A high-throughput screening campaign identified 4-((E)-styryl)-pyrimidin-2-ylamine (11) as a positive allosteric modulator of the metabotropic glutamate (mGlu) receptor subtype 4. An evaluation of the structure-activity relationships (SAR) of 11 is described and the efficacy of this compound in a haloperidol-induced catalepsy rat model following oral administration is presented.