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| Targets |
mGlu4 Receptor ( EC50 = 1 μM )
Lu AF32615 (TCN-238) targets the metabotropic glutamate receptor 4 (mGlu4). It acts as a positive allosteric modulator (PAM), meaning it binds to an allosteric site on the receptor and enhances the receptor's response to its endogenous agonist, glutamate. The compound is selective for mGlu4, with no significant activity at 68 other targets including adenosine A2A and 5-HT1A receptors. |
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| ln Vitro |
TCN238 (Compound 11) has an EC50 of 1 μM in the rat mGlu4 PAM in vitro assay, which is similar to the human assay. The IC50 of 11 is greater than 30 μM for human mGlu5 and greater than 10 μM for rat mGlu5 in the assays used to screen TCN238. When TCN238 is used in a receptor screening panel with 68 targets, none of the receptors exhibit any activity at ≥50% at 10 μM. TCN238 is reported to have good permeability in CaCo-2 cells and no obvious efflux problem[1].
In vitro, Lu AF32615 (TCN-238) acts as a positive allosteric modulator of the mGlu4 receptor with an EC₅₀ of 1 μM in functional assays using human recombinant mGlu4 receptors expressed in CHO-K1 cells. It exhibits 30-fold selectivity over mGlu5. The compound shows no significant activity at mGlu1, mGlu2, or mGlu4 receptors. It is soluble in DMSO (up to 100 mM) and ethanol (up to 10 mM). |
| ln Vivo |
TCN238 has a concentration of 33.8 μM in the brain, making it a highly CNS penetrant drug. In rats, 90% bound plasma protein binding is used as a measurement. TCN238's metabolic stability is evaluated in rat and human microsomes, and the results show that it is 62% and 83% hepatic blood flow, respectively. When administered intravenously at a dose of 2 mg/kg, TCN238 has a moderate volume of distribution (2.7 L/kg) and a short mean residence time (0.6 h). In rats, the limited stability translated into a high in vivo clearance of 75 mL/min/kg. TCN238 can be taken orally and is found to be bioavailable; 30 minutes after a dose of 30 mg/kg, the plasma concentration is 11.6 μM[1]. TCN 238 has no effect on how well the learnt task is performed. But five days after TCN 238 treatment, the hippocampus's GRM4 expression level is consistently down-regulated. Furthermore, five days following treatment, the frontal cortex's expression level of GABRA1, which codes for the GABAA α-subunit, is downregulated[2].
In vivo, Lu AF32615 (TCN-238) demonstrates oral bioavailability and high CNS penetration. It reaches a brain concentration of 33.8 μM. The compound has an ED₅₀ of approximately 1 mg/kg in Parkinson's disease models. It downregulates GRM4/GABRA1 without impairing memory. In rats, it shows 90% plasma protein binding. |
| Enzyme Assay |
Non-cellular receptor binding assays for Lu AF32615 involve radioligand displacement using membrane preparations expressing the mGlu4 receptor. Membranes are incubated with a radiolabeled mGlu4 ligand and varying concentrations of the compound. EC₅₀ values for receptor potentiation are determined using functional assays that measure receptor activation in response to glutamate in the presence of the compound.
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| Cell Assay |
In vitro cellular experiments involve cells expressing human recombinant mGlu4 receptors, such as CHO-K1 cells. Cells are treated with Lu AF32615 at various concentrations in the presence of a submaximal concentration of glutamate. Receptor activation is measured by downstream signaling such as cAMP accumulation or calcium flux. EC₅₀ values for potentiation are calculated from dose-response curves.
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| Animal Protocol |
Rats: TCN 238 is injected subcutaneously four times in two days (morning and evening) at a dose of 2 mg/kg (0.5 mL). The test of retrieval of the task is conducted five days following the final injection of TCN 238 and thirty minutes following the first and third injections. The animals are placed in front of the start box, the door is opened, and the latent period of response is recorded during the retrieval test. [2].
In vivo animal studies involve rodent models of motor dysfunction, such as Parkinson's disease models. Lu AF32615 is administered orally. Efficacy is assessed by behavioral tests measuring motor function. Brain penetration is confirmed by measuring compound levels in brain tissue. The compound's effects on memory are also evaluated. |
| ADME/Pharmacokinetics |
Lu AF32615 (TCN-238) is orally bioavailable and brain-penetrant. It has a molecular weight of 197.24 g/mol and a molecular formula of C₁₂H₁₁N₃. The compound reaches a brain concentration of 33.8 μM. It shows 90% plasma protein binding in rats. Solubility: soluble in DMSO (100 mM) and ethanol (10 mM).
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| Toxicity/Toxicokinetics |
Specific toxicity data for Lu AF32615 is limited. As a selective mGlu4 PAM, it is expected to have on-target effects related to glutamate signaling modulation. The compound is for research purposes only and should be handled with appropriate safety precautions.
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| References |
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| Additional Infomation |
Lu AF32615 (TCN-238) is an orally bioavailable, brain-penetrant positive allosteric modulator of the mGlu4 receptor with an EC₅₀ of 1 μM. It exhibits 30-fold selectivity over mGlu5 and shows efficacy in Parkinson's disease models with an ED₅₀ of approximately 1 mg/kg. The compound is used in neuroscience research for studying mGlu4 receptor function. This product is for research purposes only and is not for human therapeutic use.
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| Molecular Formula |
C12H11N3
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| Molecular Weight |
197.24
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| Exact Mass |
197.095
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| Elemental Analysis |
C, 73.07; H, 5.62; N, 21.30
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| CAS # |
125404-04-8
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| Related CAS # |
125404-04-8
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| PubChem CID |
46911068
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| Appearance |
White to off-white solid powder
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| LogP |
2.159
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
15
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| Complexity |
209
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| Defined Atom Stereocenter Count |
0
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| SMILES |
NC1=NC=CC(/C=C/C2=CC=CC=C2)=N1
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| InChi Key |
LNUXNUNUGIHCPA-VOTSOKGWSA-N
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| InChi Code |
InChI=1S/C12H11N3/c13-12-14-9-8-11(15-12)7-6-10-4-2-1-3-5-10/h1-9H,(H2,13,14,15)/b7-6+
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| Chemical Name |
4-[(E)-2-phenylethenyl]pyrimidin-2-amine
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| Synonyms |
Lu AF32615; Lu AF-32615; Lu AF 32615; Lu-AF32615; LuAF32615; TCN-238; TCN 238; TCN238
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| HS Tariff Code |
2934.99.03.00
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ≥ 150 mg/mL (~760.5 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 5.0700 mL | 25.3498 mL | 50.6997 mL | |
| 5 mM | 1.0140 mL | 5.0700 mL | 10.1399 mL | |
| 10 mM | 0.5070 mL | 2.5350 mL | 5.0700 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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