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Purity: ≥98%
FTIDC is a novel, orally bioactive, highly potent and selective negative allosteric modulator/antagonist of metabotropic glutamate receptor (mGluR) 1 with anxiolytic and antipsychotic effects. It blocks mGlu1 and mGlu5 with IC50 of 5.8 and 6200 nM, respectively. It may have therapeutic value for both humans and animal models. In the absence of ligand, it also functions as an inverse agonist of the mGlu1 receptor (IC50 = 7 nM). FTIDC inhibits L-glutamate-induced increases in intracellular calcium in mGlu1-expressing CHO cells and shows no effect at group II/III mGlu receptors. In vivo, it shows anxiolytic and antipsychotic effects in addition to inhibiting nociceptive behavior.
| Targets |
mGluR1a ( IC50 = 5.8 nM ); mGlu5 ( IC50 = 6200 nM )
Metabotropic glutamate receptor 1 (mGluR1) (human mGluR1a: IC50=5.8 nM; rat mGluR1a: IC50=5.8 nM; mouse mGluR1a: IC50=5.8 nM); Human mGluR5 (IC50=6200 nM); No agonistic, antagonistic, or positive allosteric modulatory activity toward mGluR2, mGluR4, mGluR6, mGluR7, or mGluR8 at 10 μM; Does not displace [(3)H]l-quisqualate binding to human mGluR1a [1] |
|---|---|
| ln Vitro |
FTIDC has IC50 values of 5.8 nM, 5.8 nM, 3.1 nM, and 7.7 nM for human mGluR1a, rat mGluR1a, mouse mGluR1a, and human mGluR1b in CHO cells, respectively, indicating that it inhibits the increase in intracellular Ca2+ concentrations caused by L-glutamate[1].
1. FTIDC inhibits L-glutamate-induced intracellular Ca²⁺ mobilization in Chinese hamster ovary (CHO) cells expressing human, rat, or mouse mGluR1a with equal potency, and the IC50 value for human mGluR1a is 5.8 nM [1] 2. The IC50 value of FTIDC for human mGluR5 is 6200 nM, showing a significant selectivity for mGluR1 over mGluR5 [1] 3. In the presence of higher concentrations of FTIDC, the maximal response in agonist concentration-response curves of mGluR1 was reduced, indicating that FTIDC inhibits mGluR1 in a noncompetitive manner [1] 4. FTIDC at a concentration of 10 μM exhibited no agonistic, antagonistic, or positive allosteric modulatory activity toward mGluR2, mGluR4, mGluR6, mGluR7, or mGluR8 [1] 5. FTIDC did not displace the binding of [(3)H]l-quisqualate to human mGluR1a, confirming that it acts as an allosteric antagonist of mGluR1 [1] 6. Studies using chimeric and mutant receptors of mGluR1 revealed that transmembrane (TM) domains 4 to 7, especially Phe801 in TM6 and Thr815 in TM7 of mGluR1, play pivotal roles in the antagonistic effect of FTIDC [1] 7. FTIDC inhibited the constitutive activity of mGluR1a, suggesting that it functions as an inverse agonist of mGluR1a [1] |
| ln Vivo |
FTIDC (i.p. or p.o.; 1-30 mg/kg) exhibits a statistically significant inhibitory effect on the duration of face-washing behavior elicited in a dose-dependent manner at doses of 10 and 30 mg/kg with i.p. and 30 mg/kg with p.o.[1].
1. Intraperitoneally administered FTIDC inhibited the face-washing behavior in mice elicited by the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine, and the doses used did not produce motor impairment in mice [1] 2. Orally administered FTIDC also effectively inhibited the (S)-3,5-dihydroxyphenylglycine-induced face-washing behavior in mice [1] |
| Enzyme Assay |
1. To determine the inhibitory activity of FTIDC on mGluR1-mediated Ca²⁺ mobilization, CHO cells expressing human, rat, or mouse mGluR1a were incubated with L-glutamate to induce intracellular Ca²⁺ elevation, and different concentrations of FTIDC were added to the reaction system. The changes in intracellular Ca²⁺ levels were measured to calculate the IC50 values of FTIDC for different species of mGluR1a [1]
2. To evaluate the receptor binding property of FTIDC, a radioligand binding assay was performed by incubating human mGluR1a-expressing membranes with [(3)H]l-quisqualate in the presence of FTIDC, and the amount of bound radioligand was detected to determine whether FTIDC displaces the binding of [(3)H]l-quisqualate to mGluR1a [1] 3. To investigate the molecular mechanism of FTIDC's antagonism, chimeric receptors of mGluR1 and other mGluR subtypes were constructed, and mutant mGluR1 receptors with alterations in specific transmembrane residues (including Phe801 in TM6 and Thr815 in TM7) were generated. These recombinant receptors were expressed in CHO cells, and the inhibitory effect of FTIDC on Ca²⁺ mobilization induced by L-glutamate was tested to identify the key domains and residues involved in the antagonism [1] 4. To assess the inverse agonistic activity of FTIDC, CHO cells expressing mGluR1a were cultured without L-glutamate stimulation, and different concentrations of FTIDC were added. The constitutive activity of mGluR1a was measured by detecting intracellular Ca²⁺ levels to determine whether FTIDC inhibits the basal activity of mGluR1a [1] |
| Cell Assay |
1. CHO cells stably expressing human, rat, or mouse mGluR1a were cultured in a suitable medium. The cells were stimulated with L-glutamate to trigger intracellular Ca²⁺ mobilization, and then FTIDC at various concentrations was added to the cell culture. The intracellular Ca²⁺ concentration was measured using fluorescence-based detection methods to evaluate the inhibitory effect of FTIDC and calculate the corresponding IC50 values [1]
2. CHO cells expressing mGluR2, mGluR4, mGluR6, mGluR7, or mGluR8 were prepared, and FTIDC was added to the cell culture at a concentration of 10 μM. The cellular responses related to receptor activation, inhibition, or modulation were detected to determine whether FTIDC has agonistic, antagonistic, or positive allosteric modulatory effects on these receptors [1] 3. CHO cells expressing human mGluR5 were cultured and stimulated with L-glutamate, and FTIDC at different concentrations was added to the cell system. The intracellular Ca²⁺ mobilization was measured to calculate the IC50 value of FTIDC for mGluR5 [1] 4. CHO cells expressing mGluR1a were cultured under basal conditions (without L-glutamate stimulation), and FTIDC was added to the cells. The intracellular Ca²⁺ levels were monitored to assess the effect of FTIDC on the constitutive activity of mGluR1a [1] |
| Animal Protocol |
Male CD1 (ICR) mice of 6-weeks-old
1, 3, 10, and 30 mg/kg I.p. or p.o. 1. Face-washing behavior assay in mice: Group I mGluR agonist (S)-3,5-dihydroxyphenylglycine was administered to ICR mice to elicit face-washing behavior. FTIDC was first administered to the mice via intraperitoneal injection at doses that did not cause motor impairment, and the occurrence and duration of face-washing behavior in the mice were observed and recorded [1] 2. Oral administration assay for face-washing behavior: After inducing face-washing behavior in mice with (S)-3,5-dihydroxyphenylglycine, FTIDC was administered to the mice by oral gavage, and the inhibitory effect of FTIDC on the induced face-washing behavior was evaluated by observing the behavioral changes of the mice [1] 3. Motor impairment assessment: Mice were administered with FTIDC at the doses used for the face-washing behavior assay, and their motor activity was evaluated through relevant behavioral tests to confirm whether FTIDC produces motor impairment [1] |
| Toxicity/Toxicokinetics |
1. At doses that inhibit (S)-3,5-dihydroxyphenylglycine-induced face-washing behavior (intraperitoneal and oral administration), FTIDC did not cause motor dysfunction in mice [1]
|
| References | |
| Additional Infomation |
1. FTIDC is a newly discovered highly efficient and selective allosteric glutamate receptor 1 (mGluR1) antagonist with oral activity[1]
2. FTIDC showed no species-specific antagonistic activity against recombinant human, mouse, and rat mGluR1a[1] 3. FTIDC acts as an inverse agonist of mGluR1a due to its inhibitory effect on the constitutive activity of mGluR1a[1] 4. FTIDC is a valuable tool compound for elucidating the function of mGluR1, applicable not only to rodents but also to humans[1] 5. FTIDC's antagonistic effect against mGluR1 depends on transmembrane domains 4 to 7 of mGluR1, with Phe801 in TM6 and Phe801 in TM8 being key amino acids. Thr815 plays a key role in TM7[1] |
| Molecular Formula |
C18H23FN6O
|
|---|---|
| Molecular Weight |
358.41322
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| Exact Mass |
358.191
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| Elemental Analysis |
C, 60.32; H, 6.47; F, 5.30; N, 23.45; O, 4.46
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| CAS # |
873551-53-2
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| PubChem CID |
11245287
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| Appearance |
Solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
558.2±60.0 °C at 760 mmHg
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| Flash Point |
291.4±32.9 °C
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| Vapour Pressure |
0.0±1.5 mmHg at 25°C
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| Index of Refraction |
1.624
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| LogP |
2.15
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
26
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| Complexity |
542
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1C(N2C(C)=C(C3=CCN(C(N(C)C(C)C)=O)CC3)N=N2)=CC=CN=1
|
| InChi Key |
CJTLKLBSIFQKNT-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C18H23FN6O/c1-12(2)23(4)18(26)24-10-7-14(8-11-24)16-13(3)25(22-21-16)15-6-5-9-20-17(15)19/h5-7,9,12H,8,10-11H2,1-4H3
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| Chemical Name |
4-[1-(2-fluoropyridin-3-yl)-5-methyltriazol-4-yl]-N-methyl-N-propan-2-yl-3,6-dihydro-2H-pyridine-1-carboxamide
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| Synonyms |
FTIDC
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| HS Tariff Code |
2934.99.9001
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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: ≥ 100 mg/mL (~279.0 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.98 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.98 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7901 mL | 13.9505 mL | 27.9010 mL | |
| 5 mM | 0.5580 mL | 2.7901 mL | 5.5802 mL | |
| 10 mM | 0.2790 mL | 1.3951 mL | 2.7901 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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