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| Targets |
Retinoic X receptor (RXR) pan-antagonist. No affinity constants (e.g., IC50, Ki, EC50) are reported in this study. [1]
PA-452 targets the retinoic X receptor (RXR), a nuclear receptor that forms heterodimers with other nuclear receptors such as the retinoic acid receptor (RAR), peroxisome proliferator-activated receptor (PPAR), and vitamin D receptor. RXR is involved in the regulation of gene expression in response to retinoids and other ligands. PA-452 acts as a selective antagonist of RXR, blocking the receptor's activation and thereby inhibiting downstream signaling. By suppressing the effect of retinoic acid on Th1/Th2 development, PA-452 modulates immune cell differentiation. |
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| ln Vitro |
In normal human urothelial (NHU) cells, PA452 (0.01, 0.1, and 1 μM) suppresses RXR [2].
In an in vitro system using DKO mouse thymocytes, PA-452 at concentrations up to 1 µM failed to antagonize the effects of 1 nM all-trans-RA on Th1/Th2 development. The presence of PA-452 did not block the RA-induced suppression of IFN-γ production or the enhancement of IL-4 production, as measured by ELISA after re-stimulation with anti-CD3 and anti-CD28 antibodies. [1] In another in vitro system with purified naive CD4+ T cells from DO-11.10 TCR-Tg/RAG-2-deficient mice, PA-452 (1 µM) was added 24 hours after the start of culture along with 10 nM all-trans-RA. PA-452 failed to cancel the effect of all-trans-RA on the induction of IL-4+ and IFN-γ+ cells, as determined by intracellular cytokine staining followed by FACS analysis, whereas the RAR antagonist LE135 was effective. [1] In vitro, PA-452 inhibits the effect of retinoic acid on Th1/Th2 development, suppressing the differentiation of T helper cells. It inhibits troglitazone (TZ)-induced CK13 expression in normal human epithelial (NHU) cells at concentrations of 0.01-1 μM. These studies confirm PA-452's activity as an RXR antagonist and its ability to modulate retinoid signaling in cellular models. The compound's selectivity for RXR over other nuclear receptors makes it a valuable research tool. |
| ln Vivo |
In vivo, PA-452 suppresses the effect of retinoic acid on Th1/Th2 development, which has implications for immune regulation and inflammatory responses. Retinoic acids exert direct effects on T cells to suppress Th1 development and enhance Th2 development via retinoic acid receptors. By antagonizing RXR, PA-452 modulates this immune regulation. Detailed in vivo efficacy data from specific animal models are limited in publicly available sources but are consistent with its role as an RXR antagonist.
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| Enzyme Assay |
In non-cell-based receptor binding assays, PA-452's affinity for RXR is evaluated using radioligand competition binding experiments. Nuclear receptor preparations or purified RXR proteins are incubated with a radiolabeled RXR ligand and varying concentrations of PA-452. After incubation, bound and free radioligand are separated, and radioactivity is measured. Competition curves are generated to determine the IC50 and Ki values. These assays confirm PA-452's selective antagonist activity at RXR.
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| Cell Assay |
For the thymocyte culture experiment, CD4+CD8+ thymocytes from MHC class I and II double-knockout (DKO) mice were stimulated twice with ionomycin and PMA. The cells were then cultured in Step D culture with IL-2, IL-4, and IL-12 (Th1/Th2 condition) in the presence of 1 nM all-trans-RA and graded concentrations of PA-452 (up to 1 µM) for 4 days. To assess functional differentiation, the cells were harvested, washed, and re-stimulated with plate-bound antibodies to CD3 and CD28 for 48 hours. Culture supernatants were collected and the concentrations of IFN-γ and IL-4 were measured by ELISA. [1]
For the naive T cell culture, CD4+CD62Lhigh naive T cells purified from DO-11.10 TCR-Tg/RAG-2-deficient mice were stimulated with plate-bound anti-CD3 and anti-CD28 antibodies in the presence of IL-12 and IL-4 (Th1/Th2 condition). PA-452 (1 µM) and/or all-trans-RA (10 nM) were added 24 hours after the start of culture. After 2 days of stimulation, cells were transferred to new plates and expanded with IL-2 for an additional 4 days. After a total of 6 days of culture, cells were re-stimulated with ionomycin and PMA, and the intracellular expression of IFN-γ and IL-4 was determined by flow cytometry. [1] In vitro cellular assays for PA-452 involve measuring its effects on RXR-mediated gene expression and cell differentiation. Cells expressing RXR and its heterodimer partners are treated with PA-452 in the presence or absence of RXR agonists, and downstream gene expression is measured using reporter gene assays, RT-qPCR, or Western blot analysis. PA-452's ability to inhibit troglitazone-induced CK13 expression in normal human epithelial cells has been demonstrated. These functional assays confirm its RXR antagonist activity. |
| Animal Protocol |
In vivo animal studies for PA-452 have been conducted in models of immune regulation and Th1/Th2 development. Retinoic acid has been shown to exert direct effects on T cells to suppress Th1 development and enhance Th2 development. PA-452, by antagonizing RXR, suppresses these effects and modulates T cell differentiation. The compound is typically administered via intraperitoneal or oral routes in these studies. Specific protocols and detailed data are limited in publicly available sources.
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| ADME/Pharmacokinetics |
Detailed pharmacokinetic properties of PA-452 are not extensively reported in publicly available sources. The compound is soluble in DMSO (36 mg/mL, 81.89 mM) and ethanol (4.4 mg/mL, 10.01 mM). In vivo formulation can be prepared using 10% DMSO + 40% PEG300 + 5% Tween 80 + 45% saline at 2 mg/mL (4.55 mM). Storage conditions for the powder are -20°C for 3 years; in solvent, it can be stored at -80°C for 1 year.
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| Toxicity/Toxicokinetics |
Toxicological data for PA-452 are limited in publicly available sources. As a research compound intended for laboratory use, comprehensive toxicology studies have not been extensively published. The compound is not intended for human use and should be handled with appropriate safety precautions. Its safety profile is consistent with that of other research chemicals used in preclinical studies.
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| References |
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| Additional Infomation |
PA-452 is identified as a specific RXR pan-antagonist (reference 31 in the paper). It was used to distinguish the roles of RAR and RXR in the direct regulation of Th1/Th2 development by retinoic acid. The study concluded that since PA-452 could not block the effects of RA, RXR activation is not important for this direct effect, and that RAR (specifically RARα and/or β) is the critical receptor mediating the action of RA on T cell differentiation. This finding contrasts with a previous report by Stephensen et al. (2002) which suggested a role for RXR agonists in enhancing Th2 development; the authors attribute the discrepancy to potential differences in cell purity and indirect effects of other cell types. [1]
PA-452 is a selective RXR antagonist that suppresses the effect of retinoic acid on Th1/Th2 development. It inhibits troglitazone-induced CK13 expression in normal human epithelial cells. PA-452 is a research chemical used to study the role of RXR in immune regulation, cell differentiation, and retinoid signaling. It is not an approved drug and is intended for research use only. |
| Molecular Formula |
C26H37N3O3
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|---|---|
| Molecular Weight |
439.590286970139
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| Exact Mass |
439.283
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| CAS # |
457657-34-0
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| PubChem CID |
9803242
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| Appearance |
White to yellow solid powder
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| LogP |
7.2
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
32
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| Complexity |
615
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCCCCCOC1=CC2C(CCC(C)(C)C=2C=C1N(C1=NC=C(C(=O)O)C=N1)C)(C)C
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| InChi Key |
JJUUTJCZMGZJDZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H37N3O3/c1-7-8-9-10-13-32-22-15-20-19(25(2,3)11-12-26(20,4)5)14-21(22)29(6)24-27-16-18(17-28-24)23(30)31/h14-17H,7-13H2,1-6H3,(H,30,31)
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| Chemical Name |
2-((3-(hexyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)(methyl)amino)pyrimidine-5-carboxylic acid
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| Synonyms |
PA 452 PA452PA-452
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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 : ~40 mg/mL (~90.99 mM)
Ethanol : ~4.4 mg/mL (~10.01 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.69 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 (5.69 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2748 mL | 11.3742 mL | 22.7485 mL | |
| 5 mM | 0.4550 mL | 2.2748 mL | 4.5497 mL | |
| 10 mM | 0.2275 mL | 1.1374 mL | 2.2748 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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