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| Targets |
RTI-7470-44 targets the human trace amine-associated receptor 1 (hTAAR1), a G protein-coupled receptor (GPCR) that is activated by endogenous trace amines such as β-phenylethylamine and tyramine. TAAR1 is expressed in brain regions involved in dopaminergic signaling, including the ventral tegmental area (VTA) and substantia nigra, and plays a modulatory role in dopamine neurotransmission. RTI-7470-44 is a potent antagonist of hTAAR1 with IC50 = 8.4 nM in cAMP functional assays and Ki = 0.3 nM in radioligand binding assays. The compound exhibits species selectivity for human TAAR1 over rat and mouse orthologs (>90-fold), which is important for interpreting results from animal models. By antagonizing TAAR1, RTI-7470-44 increases the spontaneous firing rate of VTA dopaminergic neurons, as TAAR1 activation typically inhibits dopamine neuron firing. This mechanism makes the compound useful for studying the role of TAAR1 in dopamine-related disorders including schizophrenia, drug addiction, and Parkinson's disease.
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| ln Vitro |
While inhibiting benzylpiperazine (BZP) rat brain site and human sigma 2 by 75% and 90%, respectively, RTI-7470-44 (10 μM) demonstrated no off-target activity; against BZP rat brain site, it had medium affinity (Ki=1 μM) and very weak affinity to human sigma 2 (Ki=8.4 μM) [1].
In vitro, RTI-7470-44 demonstrates potent and selective hTAAR1 antagonism with IC50 = 8.4 nM in cAMP functional assays and Ki = 0.3 nM in radioligand binding assays. The compound shows >90-fold selectivity for human TAAR1 over rat and mouse orthologs, indicating species-specific activity. RTI-7470-44 has moderate metabolic stability and a favorable preliminary off-target profile, suggesting good selectivity for TAAR1 over other targets. In electrophysiological studies, RTI-7470-44 (40 µM) significantly increases the firing rate of dopaminergic neurons in VTA slices from DAT-IRES-Cre; td-Tomato mice, and reverses the inhibitory effect of RO5166017 (a TAAR1 agonist). This confirms that the compound acts as a TAAR1 antagonist in functional cellular assays. The compound's ability to increase dopamine neuron firing rate is consistent with the role of TAAR1 as a negative modulator of dopaminergic activity. |
| ln Vivo |
In VTA slices of DAT-IRES-Cre; td-Tomato mice, RTI-7470-44 (40 μM) dramatically increases the firing rate of dopaminergic neurons and reverses the inhibitory effects of TAAR1 agonist RO5166017 [1]. In human liver microsomes, RTI-7470-44 (10 μM) exhibits good stability; in mouse liver microsomes, it has poor stability, and in rat liver microsomes, it has very poor stability [1]. RTI-7470-44 stability in liver microsomes from humans, rats, and mice [1]. Animal Half-life (minutes) CLINT (mL/min/mg) Rat 9.11 274 Mouse 65.8 63.5 Human 83.9 14.9
In vivo, RTI-7470-44 increases the spontaneous firing rate of dopaminergic neurons in the ventral tegmental area (VTA) of the mouse midbrain. The compound's ability to penetrate the blood-brain barrier (BBB) is essential for its central nervous system activity. By antagonizing TAAR1, RTI-7470-44 disinhibits dopaminergic neurons, leading to increased dopamine release in target brain regions. This mechanism has implications for studying schizophrenia (where dopaminergic hyperactivity is implicated), drug addiction (where dopamine plays a central role in reward and reinforcement), and Parkinson's disease (where dopaminergic neuron loss is the primary pathology). The compound's moderate metabolic stability suggests it may have suitable pharmacokinetic properties for in vivo studies. However, specific in vivo efficacy data (e.g., behavioral studies in animal models) have not been extensively reported in publicly available sources. The compound can be used for researching these neuropsychiatric disorders. |
| Enzyme Assay |
In vitro radioligand binding assays are used to characterize RTI-7470-44's interaction with hTAAR1. The compound demonstrates Ki = 0.3 nM in these assays, indicating high affinity binding to the receptor. Competition binding experiments are performed using a radiolabeled TAAR1 ligand, and the concentration of unlabeled RTI-7470-44 required to displace 50% of the radioligand binding (IC50) is determined, from which the Ki is calculated using the Cheng-Prusoff equation. Functional assays measure cAMP accumulation in cells expressing hTAAR1; the compound inhibits TAAR1-mediated cAMP production with IC50 = 8.4 nM. Selectivity is assessed by testing the compound against a panel of related receptors and enzymes. Species selectivity (>90-fold for human over rat/mouse TAAR1) is determined using similar binding and functional assays with orthologous receptors. These in vitro assays are essential for characterizing the compound's potency, selectivity, and mechanism of action.
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| Cell Assay |
In vitro cell-based assays for RTI-7470-44 are conducted in cells expressing hTAAR1. Typical cell lines include HEK-293 or CHO cells stably or transiently transfected with hTAAR1. Cells are treated with RTI-7470-44 at various concentrations, and cAMP levels are measured using ELISA or HTRF-based assays. The compound inhibits TAAR1-mediated cAMP production with IC50 = 8.4 nM. In electrophysiological studies, VTA slices from DAT-IRES-Cre; td-Tomato mice are used to record the firing rate of dopaminergic neurons. RTI-7470-44 (40 µM) is applied to the slices, and the firing rate is measured by whole-cell patch-clamp recording. The compound significantly increases the firing rate and reverses the inhibitory effect of the TAAR1 agonist RO5166017. These cell-based assays confirm the compound's functional antagonism at TAAR1 and its effects on dopaminergic neuron activity.
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| Animal Protocol |
In vivo animal experiments with RTI-7470-44 have not been extensively documented in publicly available literature. Based on the compound's mechanism of action as a TAAR1 antagonist with BBB penetration, typical study designs would involve administration of RTI-7470-44 to rodents (mice or rats) via appropriate routes (oral, intraperitoneal, intravenous, or subcutaneous). Doses would be determined from in vitro potency and pharmacokinetic data. Endpoints would include measurement of dopamine levels in brain regions (e.g., VTA, nucleus accumbens, prefrontal cortex) by microdialysis or HPLC, assessment of behavioral changes (locomotor activity, prepulse inhibition, social interaction), and evaluation of effects in disease models (e.g., amphetamine-induced hyperactivity for schizophrenia models, self-administration for addiction models, 6-OHDA lesion models for Parkinson's disease). The compound's moderate metabolic stability suggests it may be suitable for in vivo studies, but empirical data are needed.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of RTI-7470-44 include moderate metabolic stability and good blood-brain barrier (BBB) permeability, which are essential for its activity as a CNS-targeted compound. The compound's ability to penetrate the BBB enables it to reach its target (TAAR1) in the brain. The compound has a favorable preliminary off-target profile, suggesting good selectivity and potentially lower risk of off-target effects. Specific pharmacokinetic parameters such as half-life, Cmax, AUC, bioavailability, and clearance have not been extensively reported. The compound is soluble in DMSO and other organic solvents. Storage: powder at -20°C for 3 years, in solvent at -80°C for 1 year. The compound's molecular weight (449.84) and physicochemical properties are consistent with CNS-active compounds. Empirical pharmacokinetic studies would be needed for detailed characterization and dose optimization for in vivo studies.
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| Toxicity/Toxicokinetics |
Toxicology data for RTI-7470-44 are limited in publicly available sources. The compound has a favorable preliminary off-target profile, suggesting good selectivity for TAAR1 and potentially lower risk of off-target toxicities. However, comprehensive toxicology studies (acute and chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, CNS toxicity) have not been extensively reported. The compound is for research use only and is not approved for human therapeutic use. Standard laboratory safety precautions should be followed when handling RTI-7470-44. The compound should be stored properly and disposed of in accordance with applicable regulations. Researchers should consult the material safety data sheet (MSDS) for detailed safety information. As a CNS-active compound, potential pharmacological effects at high doses include alterations in behavior, motor function, and dopamine-related effects. Appropriate safety monitoring should be conducted in in vivo studies.
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| References | |
| Additional Infomation |
RTI-7470-44 is a potent, selective hTAAR1 antagonist with CAS number 825658-63-7, molecular formula C19H11ClF3N5OS, and molecular weight 449.84. The compound inhibits hTAAR1 with IC50 = 8.4 nM in cAMP functional assays and Ki = 0.3 nM in radioligand binding assays. It exhibits >90-fold selectivity for human TAAR1 over rat and mouse orthologs. RTI-7470-44 is BBB-permeable and increases the spontaneous firing rate of VTA dopaminergic neurons. The compound has moderate metabolic stability and a favorable preliminary off-target profile. It is used for researching schizophrenia, drug addiction, and Parkinson's disease. SMILES: O=C(NC1=NC=CC=N1)CSC2=NC(C3=CC=C(Cl)C=C3)=CC(C(F)(F)F)=C2C#N. Storage: powder at -20°C for 3 years, in solvent at -80°C for 1 year. Purity: typically ≥98%. Not approved for clinical use; for research purposes only. The compound is a valuable tool for studying TAAR1 biology and its role in neuropsychiatric disorders.
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| Molecular Formula |
C19H11CLF3N5OS
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| Molecular Weight |
449.84
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| Exact Mass |
449.032
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| CAS # |
825658-63-7
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| PubChem CID |
2225078
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
4.1
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
30
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| Complexity |
631
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(NC1=NC=CC=N1)(=O)CSC1=NC(C2=CC=C(Cl)C=C2)=CC(C(F)(F)F)=C1C#N
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| InChi Key |
WHNQNKYKDSLDKM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H11ClF3N5OS/c20-12-4-2-11(3-5-12)15-8-14(19(21,22)23)13(9-24)17(27-15)30-10-16(29)28-18-25-6-1-7-26-18/h1-8H,10H2,(H,25,26,28,29)
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| Chemical Name |
2-[6-(4-chlorophenyl)-3-cyano-4-(trifluoromethyl)pyridin-2-yl]sulfanyl-N-pyrimidin-2-ylacetamide
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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 : ~20.83 mg/mL (~46.31 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 | 2.2230 mL | 11.1151 mL | 22.2301 mL | |
| 5 mM | 0.4446 mL | 2.2230 mL | 4.4460 mL | |
| 10 mM | 0.2223 mL | 1.1115 mL | 2.2230 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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