Pridopidine-ACR16-DataSheet-生命科学试剂-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEPridopidineCat. No.: HY-10684CAS No.: 346688-38-8Synonyms: ACR16; ASP2314; FR310826分式: CHNOS分量: 281.41作靶点: Dopamine Receptor作通路: GPCR/G Protein; Neuronal Signaling储存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1

2、month溶解性数据体外实验 DMSO : 50 mg/mL (177.68 mM; Need ultrasonic)Mass Solvent1 mg 5 mg 10 mg Concentration制备储备液1 mM 3.5535 mL 17.7677 mL 35.5353 mL5 mM 0.7107 mL 3.5535 mL 7.1071 mL10 mM 0.3554 mL 1.7768 mL 3.5535 mL请根据产品在不同溶剂中的溶解度，选择合适的溶剂配制储备液，并请注意储备液的保存式和期限。体内实验 请根据您的实验动物和给药式选择适当的溶解案，配制前请先配制澄清的储备液，再依次添加

3、助溶剂(为保证实验结果的可靠性，体内实验的作液，建议您现现配，当天使；澄清的储备液可以根据储存条件，适当保存；以下溶剂前的百分 指该溶剂在您配制终溶液中的体积占)：1. 请依序添加每种溶剂： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (8.88 mM); Clear solution2. 请依序添加每种溶剂： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (8.88 mM); Clear solution1/3 Master of Small

4、 Molecules 您边的抑制剂师www.MedChemEBIOLOGICAL ACTIVITY物活性 Pridopidine种多巴胺 (DA) 稳定剂，可作种低亲和的多巴胺 D2 受体 (D2R) 拮抗剂。Pridopidine 亲和作于 sigma 1受体 (S1R)，Ki 值为 70 到 80 nM，其对 D2R 的亲和约 100 倍。IC50 & Target Ki: 70-80 nM (sigma 1 receptor) 1Dopamine 1Dopamine D2 receptor 1体外研究 Pridopidine, a dopamine (DA) stabilizer, Pr

5、idopidine may be a neuromodulatory agent with neuroprotectiveproperties in Huntington disease (HD). To clarify the neuroprotective efficacy of Pridopidine and to explorethe potential underling molecular mechanism, the ability of Pridopidine is evaluated to protect cells fromapoptosis and to eventual

6、ly activate pro-survival targets. Administration of Pridopidine (150 M), the mosteffective dose, significantly reduces apoptosis in immortalized striatal knock-in cells expressing endogenouslevels of mutant Htt (STHdh111/111) and markedly enhances phosphorylation state of prosurvival kinaseERK 2.体内研

7、究 Pridopidine is known to act as a low affinity D2R antagonist. Pridopidines activity may be attributed tobinding the sigma 1 receptor (S1R), an endoplasmic reticulum (ER). To strengthen the hypothesis that theBDNF pathway is upregulated due to activation of the S1R, SD rats are treated with lower d

8、oses ofPridopidine (range 0.3-60mg/kg), and analysed the expression of seven selected genes in the BDNFpathway by qPCR. Pridopidine doses of 3 and 15mg/kg in rats occupy 572% and 852% of S1R,respectively, and both do not show occupancy of the D2R, as determined by in vivo PET imaging. Thesignificant

9、 occupancy proportion of the D2R (44-66%) is observed only at a dose of 60mg/kg. This PETstudy supports the conclusion that the upregulation of genes in rats treated with 15mg/kg Pridopidine are aresult of specific activation of the S1R. At 30mg/kg, partial/low occupancy of the D2R is at levels of 2

10、2-33%(assuming linearity), and S1R is saturated. Indeed, qPCR analysis reveals that the upregulation of EGR1(already up at 3mg/kg), EGR2, HOMER1A, KLF5, and ARC expression are upregulated at the low 15mg/kgdose and expression of CDNK1A and CEBPB are significantly upregulated from a low dose of 30mg/

11、kg(CEBPB is significantly increased at 3mg/kg but not at 15mg/kg) 1. To further confirm the beneficial effectof Pridopidine on HD motor phenotype and to elucidate whether Pridopidine may act also as neuroprotectiveagent, preclinical studies in R6/2 mice have been undertaken. Daily administration of

12、Pridopidine at a dose of5 mg/kg, the most effective dose with no adverse effects, starting at the pre-symptomatic stage at 5 weeksfor 6 weeks, significantly preserves motor function and prevents the progressive and dramatic motorworsening commonly observed in R6/2 mice. The beneficial effects of Pri

13、dopidine are maintained for about 4weeks, after which mice show a slight worsening in performing both the horizontal ladder task and the openfield. In addition, according to a Kaplan-Meier survival curve analysis, Pridopidine efficiently extends lifespanin the same mice 2.PROTOCOLCell Assay 2 Condit

14、ionally immortalized mouse striatal knock-in cells expressing endogenous levels of wild-type(STHdh7/7) or mHtt (STHdh111/111) are used. Different concentrations of Pridopidine (100, 150, 200 and2/3 Master of Small Molecules 您边的抑制剂师www.MedChemE300 M) are tested to investigate the anti-apoptotic effec

15、t of the molecule on immortalized cells cultured inserum-free medium at 39C for six hours. In NE100 experiments, cells are pre-incubated with the compound(10 M) for 2 hrs before culturing them in apoptotic conditions. At the end of each treatment, cells arecollected and incubated with FITC-conjugate

16、d Annexin V. Fluorescence Activated Cell Sorting (FACS)analysis is performed 2.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Rats 1Administration 12 Sprague Dawley (SD) male rats (n=6 per group) are treated daily by oral gavage with Pridopidine

17、 at a doseof 60mg/kg or vehicle (water) over the course of 10 days. On day 10, 90min following last drug/wateradministration, brains are removed, and quickly rinsed with cold physiological saline. The striatum of the lefthemisphere is gently extracted and immediately immerged in 1000 L of RNAlater S

18、olution in pre-labelledpolypropylene vials and stored at 4C overnight (to allow the solution to thoroughly penetrate the tissue), thenmoved to -20C until analysis. RNA is isolated from the striatum of each rat and analysed 1.Mice 2All in vivo experiments are conducted in R6/2 transgenic mice express

19、ing exon 1 of human Htt withapproximately 16010 (CAG) repeats and manifesting first symptoms around week 7, and in wild-type (WT)littermates maintained on the B6CBA strain. Animals are housed singly and maintained under a 12-hrlight/dark cycle environment in a clean facility and given free access to

20、 food pellets and water. Pridopidine isdissolved in saline (vehicle), and administered daily by intraperitoneal (i.p.) injection at a dose of 5 or 6 mg/kgper bodyweight during the light phase of the circadian rhythm. Control mice (WT and R6/2) are injected dailywith the same volume of vehicle. All the mice are singly housed in home cage. Pridopidine (5 mg/kg) isadministered to pre-symptomatic mice starting at week 5 to week 11 (6 week duration) and for symptomaticanimals starting from week 7 to week 9 (3 weeks duration) and 1 week of daily