Pimavanserin

CAS# 706779-91-1

Pimavanserin

Catalog No. BCC8065----Order now to get a substantial discount!

Product Name & Size Price Stock
Pimavanserin:5mg $64.00 In stock
Pimavanserin:10mg $109.00 In stock
Pimavanserin:25mg $256.00 In stock
Pimavanserin:50mg $448.00 In stock
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Quality Control of Pimavanserin

Quality Control & MSDS

Number of papers citing our products

Chemical structure

Pimavanserin

3D structure

Chemical Properties of Pimavanserin

Cas No. 706779-91-1 SDF Download SDF
PubChem ID 10071196 Appearance Powder
Formula C25H34FN3O2 M.Wt 427.55
Type of Compound N/A Storage Desiccate at -20°C
Synonyms ACP-103
Solubility DMSO : 50 mg/mL (116.95 mM; Need ultrasonic)
Chemical Name 1-[(4-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-[[4-(2-methylpropoxy)phenyl]methyl]urea
SMILES CC(C)COC1=CC=C(C=C1)CNC(=O)N(CC2=CC=C(C=C2)F)C3CCN(CC3)C
Standard InChIKey RKEWSXXUOLRFBX-UHFFFAOYSA-N
Standard InChI InChI=1S/C25H34FN3O2/c1-19(2)18-31-24-10-6-20(7-11-24)16-27-25(30)29(23-12-14-28(3)15-13-23)17-21-4-8-22(26)9-5-21/h4-11,19,23H,12-18H2,1-3H3,(H,27,30)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Pimavanserin

DescriptionPimavanserin is a potent 5-hydroxytryptamine (5-HT)2A receptor inverse agonist, displays potent inverse agonist activity in the cell-based functional assay receptor selection and amplification technology (R-SAT), with a mean pIC50 of 8.7.In Vitro:Pimavanserin (ACP-103) competitively antagonizes the binding of [3H]ketanserin to heterologously expressed 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, as determined by radioligand binding) and potency as an inverse agonist (mean pIC50 7.1 in R-SAT) at human 5-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-HT2A receptors, lacking affinity for other receptors in a broad profile screen including 65 different molecular targets; the only other receptor for which Pimavanserin demonstrates affinity is 5-HT2C, and Pimavanserin is approximately 30-fold selective for 5-HT2A receptors over 5-HT2C receptors depending on the assay[2].In Vivo:Pimavanserin (ACP-103) is a potent, efficacious, orally active 5-HT2A receptor inverse agonist with a behavioral pharmacological profile consistent with utility as an antipsychotic agent. Pimavanserin attenuates head-twitch behavior (3 mg/kg p.o.), and prepulse inhibition deficits (1-10 mg/kg s.c.) induced by the 5-HT2A receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride in rats and reduces the hyperactivity induced in mice by the N-methyl-D-aspartate receptor noncompetitive antagonist 5H-dibenzo[a,d]cyclohepten-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 and antipsychotic-like efficacy. Pimavanserin demonstrates >42.6% oral bioavailability in rats[1].

References:
[1]. Vanover KE, et al. Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine(2A) receptor inver [2]. Vanover KE, et al. A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model. Pharmacol Biochem Behav. 2008 Oct;90(4):540-4.

Protocol

Kinase Assay [1]
For the membrane binding, NIH-3T3 cells are grown to 70% confluence in 15 cm2 dishes and transfected with 10 μg of receptor plasmid DNA using Polyfect transfection reagent. Two days after transfection, cells expressing the desired serotonin receptor are homogenized in 20 mM HEPES/10 mM EDTA and spun down at 11,000g at 4°C for 30 min. The supernatant is discarded, and the pellet is resuspended in 20 mM HEPES/1 mM EDTA and spun down at the same setting. The pellet is then resuspended in 20 mM HEPES/0.5 mM EDTA, and membranes are used for binding assays. Bradford analysis is used to determine total membrane protein. Kd and Bmax values are derived from 12-point concentration experiments using 1 nM [3H]ketanserin for the 5-HT2A receptor and 3 nM [3H]mesulergine for the 5-HT2B and 5-HT2C receptors. Membranes are incubated at room temperature for 3 h with various concentrations of test ligand in the presence of a fixed concentration of radioligand. The suspension is filtered as explained below for whole-cell binding, washed with ice-cold buffer, and dried, and radioactivity is determined using TopCount[1].

Cell Assay [1]
For the whole-cell binding, 6 million human embryonic kidney 293T cells are plated in 10-cm dishes and transfected with 5 μg of plasmid DNA using Polyfect. Two days after transfection, cells are harvested with 10 mM 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 receptor are incubated at 37°C for 3 h in the presence of 5 nM radioligand ([3H]ketanserin for 5-HT2A receptors and [3H]mesulergine for 5-HT2C-INI receptors) and varying concentrations of ligands (total volume 100 μL in a 96-well plate). Cells are filtered onto a 96-well GF/B filter plate and washed with 300 mL of wash buffer (25 mM HEPES, 1 mM CaCl2, 5 mM MgCl2, and 0.25 M NaCl) using a Filtermate 196 harvester. The filter plates are dried under a heat lamp before addition of 50 μL of scintillation fluid to each well. Plates are counted on a TopCount. Separately, the hydrochloride salt form of Pimavanserin (10 μM) is evaluated at MDS Pharma Services for activity in a broad screen of radioligand binding assays at 65 different receptors[1].

Animal Administration [1]
Mice[1] Non-Swiss albino mice are used for locomotor activity experiments. For determination of spontaneous activity, Pimavanserin is administered alone (s.c. 60 min before session start or p.o. 60 min before session start). For hyperactivity experiments, mice are treated with 0.3 mg/kg MK-801 (i.p.) 15 min presession (the peak dose for producing hyperactivity in an inverted-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 lit room. Mice had no prior exposure to the motor cages. Immediately before placing the mice in the locomotor chambers, effects on myorelaxation/ataxia are determined by placing each of the mouse's forepaws in contact with a horizontal wire while holding the mouse by the base of the tail. Mice are required to bring at least one hindpaw in contact with the wire within 10 s to be scored as a “pass” and failure to do so is considered ataxic. Each dose or dose combination is tested in a separate group of mice (n=8). Rats[1] For DOI head-twitch experiments in rats, vehicle or a dose of Pimavanserin is administered orally 120 min before DOI administration. DOI HCl (2.5 mg/kg i.p.) is administered immediately before observations. After injection of DOI, each rat is placed into an empty cage and observed. Latency to the first head twitch and the number of head twitches occurring over 5 min are recorded. Each rat is used only once with eight to 16 rats per dose group.

References:
[1]. Vanover KE, et al. Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine(2A) receptor inver [2]. Vanover KE, et al. A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model. Pharmacol Biochem Behav. 2008 Oct;90(4):540-4.

Pimavanserin Dilution Calculator

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Pimavanserin Molarity Calculator

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Preparing Stock Solutions of Pimavanserin

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.3389 mL 11.6945 mL 23.3891 mL 46.7782 mL 58.4727 mL
5 mM 0.4678 mL 2.3389 mL 4.6778 mL 9.3556 mL 11.6945 mL
10 mM 0.2339 mL 1.1695 mL 2.3389 mL 4.6778 mL 5.8473 mL
50 mM 0.0468 mL 0.2339 mL 0.4678 mL 0.9356 mL 1.1695 mL
100 mM 0.0234 mL 0.1169 mL 0.2339 mL 0.4678 mL 0.5847 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Pimavanserin

Pimavanserin(ACP-103) is a potent and selective 5-HT2A receptor inverse agonist with mean pIC50 of with 8.7 in the cell-based functional assay.

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References on Pimavanserin

Pimavanserin: A Novel Antipsychotic for Parkinson's Disease Psychosis.[Pubmed:28375643]

Ann Pharmacother. 2017 Jun;51(6):479-487.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of Pimavanserin for the treatment of hallucinations and delusions of Parkinson's disease psychosis (PDP). DATA SOURCES: A comprehensive PubMed search (1966 to January 2017) was conducted using the search terms Parkinson's disease psychosis, hallucinations, delusions, Pimavanserin, and ACP-103. Additional data were obtained from references of identified articles, governmental sources, manufacturer product labeling and website, and Clinicaltrials.gov. STUDY SELECTION AND DATA EXTRACTION: All English-language trials evaluating Pimavanserin in PDP were included. Data from review articles were included if relevant to clinical practice. One phase II and 3 phase III trials are discussed. DATA SYNTHESIS: Pimavanserin was approved in April 2016 for the treatment of delusions and hallucinations of PDP. One phase II and 2 phase III trials reported no difference for primary outcomes when Pimavanserin was compared with placebo. The pivotal phase III ACP-103-020 trial adapted a scale to target more specific symptoms prevalent in PDP and showed that least-squares mean differences of the total PD-adapted Scale for the Assessment of Positive Symptoms score were significantly improved for Pimavanserin-treated patients as compared with placebo-treated patients (difference = -3.06; 95% CI [-4.91 to -1.20]; P = 0.0014]). Pimavanserin's adverse effect profile includes urinary tract infections, falls, peripheral edema, hallucinations, confusion, nausea, and headaches. CONCLUSION: Pimavanserin is a novel 5-HT2A inverse agonist that has shown promising results for managing hallucinations and delusions in patients with PDP without worsening motor effects or orthostasis. Yet its high cost and specialty pharmacy access may limit use in clinical practice.

Evidence for the use of pimavanserin in the treatment of Parkinson's disease psychosis.[Pubmed:27800022]

Ther Adv Neurol Disord. 2016 Nov;9(6):462-473.

Parkinson's disease (PD) is a progressive neurodegenerative disorder with both motor and nonmotor symptoms (NMS), leading to significant morbidity and caregiver burden. Psychosis is common but is under recognized by physicians. When present, it increases the patient's risk of hospitalization and nursing home placement and caregiver burden. Although the atypical antipsychotic agent, clozapine, has been considered the gold standard treatment, severe agranulocytosis in 0.38% of patients and more commonly milder leukopenia, resulting in frequent blood testing, limit its use. Pimavanserin, a 5HT2A receptor inverse agonist, has been shown to reduce psychosis in PD without worsening motor symptoms. It is therefore a welcome therapeutic option for this devastating NMS.

Update on the treatment of Parkinson's disease psychosis: role of pimavanserin.[Pubmed:28331324]

Neuropsychiatr Dis Treat. 2017 Mar 8;13:737-744.

Parkinson's disease (PD) has a prevalence of nearly 1 million people in the USA, with increasing incidence in the elderly population. Generally, the age of presentation is between 55 and 65 years, with the likelihood of diagnosis increasing as patients reach the age of 80 years or above. Some of the common treatments for PD increase dopamine levels in the brain. Dopaminergic therapy helps to improve motor and non-motor symptoms, but it is not without risks. Dopaminergic therapy can cause confusion, delirium, and psychotic-like behavior. It is recommended that these agents are used cautiously in patients with a history of psychosis due to the risk of exacerbation. It is unclear whether Parkinson's disease psychosis (PDP) is due to the disease itself, the treatment, or a combination of both, but it is clear that a safe, effective treatment is necessary. Second-generation (atypical) antipsychotics are the current choice of therapy for PDP. All of these agents have a black box warning from the US Food and Drug Administration (FDA) for elevated risk of mortality in elderly patients with dementia-related psychosis. Pimavanserin (Nuplazid((R))) received its novel drug approval by the FDA on April 29, 2016, to treat hallucinations and delusions associated with psychosis experienced by some people with PD. We review in this article the new research that led to this approval as well as its potential place in therapy.

Repeated 7-Day Treatment with the 5-HT2C Agonist Lorcaserin or the 5-HT2A Antagonist Pimavanserin Alone or in Combination Fails to Reduce Cocaine vs Food Choice in Male Rhesus Monkeys.[Pubmed:27857126]

Neuropsychopharmacology. 2017 Apr;42(5):1082-1092.

Cocaine use disorder is a global public health problem for which there are no Food and Drug Administration-approved pharmacotherapies. Emerging preclinical evidence has implicated both serotonin (5-HT) 2C and 2A receptors as potential mechanisms for mediating serotonergic attenuation of cocaine abuse-related neurochemical and behavioral effects. Therefore, the present study aim was to determine whether repeated 7-day treatment with the 5-HT2C agonist lorcaserin (0.1-1.0 mg/kg per day, intramuscular; 0.032-0.1 mg/kg/h, intravenous) or the 5-HT2A inverse agonist/antagonist Pimavanserin (0.32-10 mg/kg per day, intramuscular) attenuated cocaine reinforcement under a concurrent 'choice' schedule of cocaine and food availability in rhesus monkeys. During saline treatment, cocaine maintained a dose-dependent increase in cocaine vs food choice. Repeated Pimavanserin (3.2 mg/kg per day) treatments significantly increased small unit cocaine dose choice. Larger lorcaserin (1.0 mg/kg per day and 0.1 mg/kg/h) and Pimavanserin (10 mg/kg per day) doses primarily decreased rates of operant behavior. Coadministration of ineffective lorcaserin (0.1 mg/kg per day) and Pimavanserin (0.32 mg/kg per day) doses also failed to significantly alter cocaine choice. These results suggest that neither 5-HT2C receptor activation nor 5-HT2A receptor blockade are sufficient to produce a therapeutic-like decrease in cocaine choice and a complementary increase in food choice. Overall, these results do not support the clinical utility of 5-HT2C agonists and 5-HT2A inverse agonists/antagonists alone or in combination as candidate anti-cocaine use disorder pharmacotherapies.

Description

Pimavanserin is a selective inverse agonist of the 5-HT2A receptor with pIC50 and pKd of 8.73 and 9.3, respectively.

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