RTI-371
RTI-371 is a highly selective atypical dopamine transporter (DAT) inhibitor that crosses the blood-brain barrier. RTI-371 exhibits potent inhibitory activity in cell lines transfected with human DAT (IC50 = 8.7 nM) and shows high binding affinity for rat DAT with a Ki value of 7.81 nM. RTI-371 also acts as a positive allosteric modulator of the human cannabinoid 1 receptor (hCB1 receptor), enhancing the activity of cannabinoid receptor agonists in a concentration-dependent manner. RTI-371 can be used for the research of Parkinson's disease.
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- CAS. Nr.: 652978-45-5
- Formel: C24H25ClN2O
- Molecular Weight:392.92
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Speicherung:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biologische Aktivität
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Chemical Information
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- Reinheit & Dokumentation
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Biologische Aktivität
Beschreibung
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DAT 7.81 nM (Ki) |
DAT 8.7 nM (IC50) |
NET 880 nM (Ki) |
NET 3990 nM (IC50) |
SERT 50200 nM (Ki) |
SERT > 100,000 nM (IC50) |
σ1 15800 nM (Ki) |
σ2 353 nM (Ki) |
Muscarinic 1 Receptor 11000 nM (Ki) |
hCB1-R |
In Vitro
RTI-371 (1-10 μM; 15 min pre-incubation) in RD-HGA16 cells stably expressing hCB1 shows no intrinsic activity but acts as a positive allosteric modulator of CB1, increasing CP55940 efficacy by 36%, while also enhancing WIN55212-2-mediated hCB1 receptor activation[1].
RTI-371 (10 μM; 15 min pre-incubation) in RD-HGA16 cells stably expressing hMOR shows no significant effect on DAMGO(HY-P0210)-induced μ-opioid receptor signaling, further confirming its selectivity for CB1[1].
RTI-371 (1.0 and 10 μM; 20 min pre-incubation followed by 30 min co-incubation) in HEK293 cells enhances maleimide-PEO2-biotin labeling of DAT and further increases DAT labeling in mutant cells, indicating stabilization of an outward-facing DAT conformation[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
In Vivo
RTI-371 (1.0-170 mg/kg; intraperitoneal injection; single dose) in CD-1 mice and Swiss-Webster mice produces only mild to weak locomotor stimulation, characterized by delayed and low-amplitude increases in horizontal locomotor activity[1][2].
RTI-371 (3.0-100 mg/kg; intraperitoneal injection; single dose) in Swiss-Webster mice partially substitutes for neuroactive agent in a drug-discrimination assay, reaching approximately 60-68% neuroactive agent-appropriate responding and producing dose-dependent decreases in response rates[2].
RTI-371 (0.01-1.0 mg/kg/injection; intravenous injection; self-administration procedure) in male Sprague-Dawley rats does not maintain self-administration behavior, with responding remaining at saline levels, indicating lack of reinforcing effects[2].
RTI-371 (1.0-17 mg/kg; intraperitoneal injection; single dose) in male Sprague-Dawley rats dose-dependently reduces neuroactive agent self-administration and produces insurmountable antagonism, resulting in a downward shift of the dose–response curve[2].
RTI-371 (3.0-56 mg/kg; intraperitoneal injection; [125I]RTI-121 intravenous injection tracer; single dose) in Swiss-Webster mice produces dose- and time-dependent DAT occupancy in the striatum, reaching maximal binding site occupancy and exhibiting slow brain penetration kinetics[2].
RTI-371 (3.0-30 mg/kg; intraperitoneal injection; single dose) in wild-type and CB1 receptor knockout mice increases locomotor activity with no genotype-dependent differences[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Locomotor activity screening model (male CD-1 mice)[1]
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Dosage:Up to 30 mg/kg
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Administration:Intraperitoneal injection (i.p.), single dose
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Result:Displayed little or no effect on mouse horizontal locomotor activity, showing a poor correlation between locomotor stimulation and DAT inhibition.
Normalized locomotor stimulation score was reported as 5% (± 2%) of the maximum stimulation observed with 30 mg/kg cocaine.
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Animal Model:In vivo [125I]RTI-55 displacement binding model (rats)[1]
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Dosage:Up to 30 mg/kg
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Administration:Intraperitoneal injection (i.p.), single dose
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Result:Crossed the blood-brain barrier and successfully entered the central nervous system, as evidenced by its ability to displace the in vivo binding of the radioligand [125I]RTI-55 in the rat caudate.
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Animal Model:Swiss-Webster mice locomotor activity model[2]
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Dosage:1.0, 3.0, 10, 20, 30, 40, 56, 100, and 170 mg/kg
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Administration:Intraperitoneal injection (i.p.), single dose
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Result:Exhibited less effectiveness in stimulating locomotion, and was ineffective in the first 30 minutes after injection.
Increased horizontal ambulatory activity at later times over the course of the observation period to a maximum mean of 266 counts/min at the 100 mg/kg dose from 60 to 90 minutes after injection.
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Animal Model:Cocaine/saline drug-discrimination procedure in Swiss-Webster mice[2]
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Dosage:3.0, 10, 17, 30, and 56 mg/kg (for 5-min pre-session treatment); 10, 30, 56, and 100 mg/kg (for 60-min pre-session treatment)
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Administration:Intraperitoneal injection (i.p.), single dose
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Result:Incompletely substituted for cocaine, reaching a maximum of approximately 60% to 68% drug-lever responding at 5 minutes or 1 hour after injection.
Produced a level of substitution greater than that produced by saline, although some subjects showed full substitution at some doses while others showed less than 33% drug-appropriate responding.
Produced dose-related decreases in rates of responding, with decreases at 5 minutes occurring at lower doses than at 60 minutes after injection.
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Animal Model:Cocaine self-administration and substitution model in male Sprague-Dawley rats[2]
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Dosage:0.01, 0.032, 0.1, 0.32, and 1.0 mg/kg/injection (unit doses under a five-component procedure)
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Administration:Intravenous injection (i.v.), single dose
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Result:Maintained low response rates throughout the experimental session that were not different from those obtained when saline injections were available.
Maintained response rates well below those maintained by cocaine, and showed no significant differences between any dose per injection compared with the extinction component.
Demonstrated that the compound itself was not self-administered.
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Animal Model:Presession treatment on cocaine self-administration in male Sprague-Dawley rats[2]
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Dosage:1.0, 3.2, 10, and 17 mg/kg
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Administration:Intraperitoneal injection (i.p.), single dose
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Result:Dose-dependently decreased maximal cocaine self-administration more potently than food-maintained responding, with ED50 values of 3.33 mg/kg for cocaine-maintained responding and 8.21 mg/kg for food presentation.
Produced an insurmountable antagonism of cocaine self-administration, shifting the cocaine self-administration dose-effect curve downward rather than leftward.
Increased the pauses before initiation of responding and caused responding to cease before the end of the components at the 10 mg/kg dose, where no dose of cocaine maintained responding above saline levels.
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Animal Model:In vivo [125I]RTI-121 binding and DAT occupancy model in Swiss-Webster mice[2]
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Dosage:3.0, 10, 30, and 56 mg/kg
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Administration:Intraperitoneal injection (i.p.) for compound; intravenous injection (i.v.) via tail vein for [125I]RTI-121; single dose
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Result:Produced a dose- and time-related displacement of [125I]RTI-121 binding in the striatum, reaching maximum displacement with 56 mg/kg at 60 min.
Exhibited the least steep slopes fitted to the time course of displacement among tested drugs, with a displacement rate of 0.320%/min at 56 mg/kg.
Demonstrated the slowest apparent association rate and in vivo DAT occupancy among tested drugs, approximately one-half of RTI-336 and one-fourth of cocaine.
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Animal Model:Locomotor activity model in cannabinoid CB1 receptor wild-type and knockout mice[2]
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Dosage:3.0, 10, and 30 mg/kg
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Administration:Intraperitoneal injection (i.p.), single dose
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Result:Increased horizontal ambulatory activity from 60 to 90 min after injection, with maximum mean ambulatory counts of 100 and 74.4 counts/min at 30 mg/kg for wild-type and knockout mice, respectively.
Stimulated activity from 120 to 150 min after injection but was less effective.
Showed no significant effect of genotype or dose-dependent differences, indicating that cannabinoid CB1 receptors do not decrease its cocaine-like stimulation or mediate its unique effects.
Chemical Information
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CAS. Nr. 652978-45-5
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Molecular Weight 392.92
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Formel C24H25ClN2O
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SMILES
[H][C@@]12[C@H]([C@H](C[C@@](N2C)([H])CC1)C3=CC=C(C=C3)C)C4=CC(C5=CC=C(C=C5)Cl)=NO4
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Versand
Room temperature in continental US; may vary elsewhere.
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Speicherung
Please store the product under the recommended conditions in the Certificate of Analysis.
Protokoll
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Cell Cytotoxicity Assay
Cytotoxicity assays are usually based on the assessment of cell membrane damage, which can also be indirectly detected by measuring cell viability. Detection methods include MTT assay, CKK-8 assay, LDH assay and ATP assay, etc.
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Human pluripotent stem cell midbrain dopaminergic neuron differentiation
Human pluripotent stem cells are directed toward midbrain dopaminergic neurons by first inducing a neural floor-plate-like progenitor state, then patterning cells with ventralizing SHH signaling and midbrain/WNT-FGF cues, and finally maturing progenitors into neurons expressing dopaminergic markers such as TH, NURR1/NR4A2, PITX3, DAT/SLC6A3, VMAT2/SLC18A2, GIRK2/KCNJ6, FOXA2, LMX1A, and EN1. The main readouts are loss of pluripotency, acquisition of FOXA2+/LMX1A+ midbrain floor-plate progenitors, emergence of βIII-tubulin+/MAP2+ neurons, and production of TH+ dopaminergic neurons with molecular, dopamine-release, and electrophysiological features of midbrain dopaminergic identity.
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Directly Induced Neuron Culture
Directly induced neuron culture converts somatic cells, most commonly fibroblasts, into induced neurons without passing through a pluripotent or neural progenitor stage; classic evidence shows that mouse fibroblasts can be converted by Ascl1, Brn2/Pou3f2, and Myt1l, human fibroblasts can be converted by defined neuronal transcription factors, and human fibroblasts can also be converted by miR-9/9-124 with neurogenic or subtype-specifying transcription factors. The readout is acquisition of neuronal identity and function, assessed by neuronal morphology, neuronal markers such as Tuj1/βIII-tubulin, MAP2, synapsin, and subtype markers when relevant, together with functional assays such as action-potential firing, synaptic activity, and electrophysiology.
Reinheit & Dokumentation
Verweise
[1]. Navarro HA, et al. Positive allosteric modulation of the human cannabinoid (CB) receptor by RTI-371, a selective inhibitor of the dopamine transporter. Br J Pharmacol. 2009 Apr;156(7):1178-84. [Content Brief]
[2]. Hiranita T, et al. 2-isoxazol-3-phenyltropane derivatives of cocaine: molecular and atypical system effects at the dopamine transporter. J Pharmacol Exp Ther. 2014 May;349(2):297-309. [Content Brief]
Calculators
Konzentration (Stammlösung) × Volumen (Stammlösung) = Konzentration (Ziellösung) × Volumen (Ziellösung)
RTI-371 Related Classifications
HY-129215 Related Classifications
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