Pimavanserin-ACP-103-DataSheet-生命科學試劑-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEPimavanserinCat. No.: HY-14557CAS No.: 706779-91-1Synonyms: ACP-103分式: CHFNO分量: 427.55作靶點: 5-HT Receptor作通路: GPCR/G Protein; Neuronal Signaling儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實驗 DMSO

2、: 50 mg/mL (116.95 mM; Need ultrasonic)Mass Solvent1 mg 5 mg 10 mg Concentration制備儲備液1 mM 2.3389 mL 11.6945 mL 23.3891 mL5 mM 0.4678 mL 2.3389 mL 4.6778 mL10 mM 0.2339 mL 1.1695 mL 2.3389 mL請根據(jù)產(chǎn)品在不同溶劑中的溶解度，選擇合適的溶劑配制儲備液，并請注意儲備液的保存式和期限。體內(nèi)實驗請根據(jù)您的實驗動物和給藥式選擇適當?shù)娜芙獍?，配制前請先配制澄清的儲備液，再依次添加助溶?為保證實驗結果的可靠性，體內(nèi)實驗的

3、作液，建議您現(xiàn)現(xiàn)配，當天使；澄清的儲備液可以根據(jù)儲存條件，適當保存；以下溶劑前的百分 指該溶劑在您配制終溶液中的體積占)：1. 請依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (5.85 mM); Clear solution2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (5.85 mM); Clear solution3. 請依序添加每種溶劑： 10% DMSO 90% corn oil1/4 M

4、aster of Small Molecules 您邊的抑制劑師www.MedChemESolubility: 2.5 mg/mL (5.85 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 Pimavanserin是選擇性的 5-HT2A 受體反向激動劑，pIC50 和 pKd 分別為8.73 and 9.3。IC50 & Target 5-HT2A Receptor8.7 (pIC50)體外研究 Pimavanserin (ACP-103) competitively antagonizes the binding of 3Hketanserin to

5、heterologouslyexpressed human 5-HT2A receptors with a mean pKi of 9.3 in membranes and 9.70 in whole cells.Pimavanserin demonstrates lesser affinity (mean pKi of 8.80 in membranes and 8.00 in whole cells, asdetermined by radioligand binding) and potency as an inverse agonist (mean pIC50 7.1 in R-SAT

6、) at human5-HT2C receptors, and lacked affinity and functional activity at 5-HT2B receptors, dopamine D2 receptors,and other human monoaminergic receptors 1. Pimavanserin (ACP-103) is highly selective for 5-HT2Areceptors, lacking affinity for other receptors in a broad profile screen including 65 di

7、fferent molecular targets;the only other receptor for which Pimavanserin demonstrates affinity is 5-HT2C, and Pimavanserin isapproximately 30-fold selective for 5-HT2A receptors over 5-HT2C receptors depending on the assay 2.體內(nèi)研究 Pimavanserin (ACP-103) is a potent, efficacious, orally active 5-HT2A

8、receptor inverse agonist with abehavioral pharmacological profile consistent with utility as an antipsychotic agent. Pimavanserin attenuateshead-twitch behavior (3 mg/kg p.o.), and prepulse inhibition deficits (1-10 mg/kg s.c.) induced by the 5-HT2Areceptor agonist ()-2,5-dimethoxy-4-iodoamphetamine

9、 hydrochloride in rats and reduces the hyperactivityinduced in mice by the N-methyl-D-aspartate receptor noncompetitive antagonist 5H-dibenzoa,dcyclohepten-5,10-imine (dizocilpine maleate; MK-801) (0.1 and 0.3 mg/kg s.c.; 3 mg/kg p.o.),consistent with a 5-HT2A receptor mechanism of action in vivo an

10、d antipsychotic-like efficacy. Pimavanserindemonstrates 42.6% oral bioavailability in rats 1.PROTOCOLKinase Assay 1 For the membrane binding, NIH-3T3 cells are grown to 70% confluence in 15 cm2 dishes and transfectedwith 10 g of receptor plasmid DNA using Polyfect transfection reagent. Two days afte

11、r transfection, cellsexpressing the desired serotonin receptor are homogenized in 20 mM HEPES/10 mM EDTA and spun downat 11,000g at 4C for 30 min. The supernatant is discarded, and the pellet is resuspended in 20 mMHEPES/1 mM EDTA and spun down at the same setting. The pellet is then resuspended in

12、20 mMHEPES/0.5 mM EDTA, and membranes are used for binding assays. Bradford analysis is used to determinetotal membrane protein. Kd and Bmax values are derived from 12-point concentration experiments using 1nM 3Hketanserin for the 5-HT2A receptor and 3 nM 3Hmesulergine for the 5-HT2B and 5-HT2C rece

13、ptors.Membranes are incubated at room temperature for 3 h with various concentrations of test ligand in thepresence of a fixed concentration of radioligand. The suspension is filtered as explained below for whole-cellbinding, washed with ice-cold buffer, and dried, and radioactivity is determined us

14、ing TopCount 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.2/4 Master of Small Molecules 您邊的抑制劑師www.MedChemECell Assay 1 For the whole-cell binding, 6 million human embryonic kidney 293T cells are plated in 10-cm dishes andtransfected with 5 g of pl

15、asmid DNA using Polyfect. Two days after transfection, cells are harvested with 10mM EDTA, washed, and resuspended in binding buffer (1 DMEM with 0.1% bovine serum albumin). Then,60,000 cells transfected with the 5-HT2A receptor or 20,000 cells transfected with the 5-HT2C-INI receptorare incubated a

16、t 37C for 3 h in the presence of 5 nM radioligand (3Hketanserin for 5-HT2A receptors and3Hmesulergine for 5-HT2C-INI receptors) and varying concentrations of ligands (total volume 100 L in a96-well plate). Cells are filtered onto a 96-well GF/B filter plate and washed with 300 mL of wash buffer (25m

17、M HEPES, 1 mM CaCl2, 5 mM MgCl2, and 0.25 M NaCl) using a Filtermate 196 harvester. The filter platesare dried under a heat lamp before addition of 50 L of scintillation fluid to each well. Plates are counted on aTopCount. Separately, the hydrochloride salt form of Pimavanserin (10 M) is evaluated a

18、t MDS PharmaServices for activity in a broad screen of radioligand binding assays at 65 different receptors 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice 1Administration 1 Non-Swiss albino mice are used for locomotor activity experiments

19、. For determination of spontaneousactivity, Pimavanserin is administered alone (s.c. 60 min before session start or p.o. 60 min before sessionstart). For hyperactivity experiments, mice are treated with 0.3 mg/kg MK-801 (i.p.) 15 min presession (thepeak dose for producing hyperactivity in an inverte

20、d-U dose-effect curve as determined in pilot experiments)in combination with vehicle or Pimavanserin. Motor activity data are collected during a 15-min session in a litroom. Mice had no prior exposure to the motor cages. Immediately before placing the mice in the locomotorchambers, effects on myorel

21、axation/ataxia are determined by placing each of the mouses forepaws incontact with a horizontal wire while holding the mouse by the base of the tail. Mice are required to bring atleast one hindpaw in contact with the wire within 10 s to be scored as a “pass” and failure to do so isconsidered ataxic

22、. Each dose or dose combination is tested in a separate group of mice (n=8).Rats 1For DOI head-twitch experiments in rats, vehicle or a dose of Pimavanserin is administered orally 120 minbefore DOI administration. DOI HCl (2.5 mg/kg i.p.) is administered immediately before observations. Afterinjecti

23、on of DOI, each rat is placed into an empty cage and observed. Latency to the first head twitch and thenumber of head twitches occurring over 5 min are recorded. Each rat is used only once with eight to 16 ratsper dose group.MCE has not independently confirmed the accuracy of these methods. They are for reference only.戶使本產(chǎn)品發(fā)表的科研獻 Department Neuroscience. Virginia Commonwealth University. 2016 Oct.S