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Purity: ≥98%
Pimavanserin (formerly ACP-103; BVF-036; trade name Nuplazid) is an orally bioactive and selective inverse agonist of the 5-HT2A (serotonin receptor subtype 2A, pIC50 and pKd of 8.73 and 9.3, respectively) receptor approved as an atypical antipsychotic for the treatment of Parkinson's disease psychosis. Psychosis, schizophrenia, agitation, major depressive disorder, and Alzheimer's disease are among the other conditions for which it is being studied. In rats, ACP-103 decreased the tremulous jaw movements brought on by tacrine. Furthermore, there was a dose-related decrease in monkey dyskinesias when ACP-103 and levodopa were given together. According to these findings, ACP-103 might be able to lessen Parkinson's disease-related tremor and levodopa-induced dyskinesias.
| Targets |
5-HT2A Receptor ( pIC50 = 8.7 )
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| ln Vitro |
Pimavanserin (ACP-103) has a mean pKi of 9.3 in membranes and 9.70 in whole cells, which competitively opposes [3H]ketanserin's binding to heterologously expressed human 5-HT2A receptors. The results of radioligand binding indicate that pimavanserin has lower potency and affinity as an inverse agonist (mean pIC50 7.1 in R-SAT) at human 5-HT2C receptors (mean pKi of 8.80 in membranes and 8.00 in whole cells). It also shows no affinity or functional activity at 5-HT2B receptors, dopamine D2 receptors, or other human monoaminergic receptors[1]. Pimavanserin (ACP-103) exhibits a strong preference for 5-HT2A receptors and lacks affinity for other receptors in a broad profile screen that includes 65 distinct molecular targets. Pimavanserin only shows affinity for 5-HT2C receptors, and depending on the assay, it is roughly 30-fold more selective for 5-HT2A receptors than 5-HT2C receptors[2].
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| ln Vivo |
Pimavanserin (also known as ACP-103) is a strong, effective, and orally active inverse agonist of the 5-HT2A receptor with a behavioral pharmacological profile that supports its use as an antipsychotic medication. Pimavanserin 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 attenuates head-twitch behavior (3 mg/kg p.o.) and prepulse inhibition deficits (1–10 mg/kg s.c.) induced in rats. In rats, pimavanserin exhibits an oral bioavailability of >42.6%[1].
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| Enzyme Assay |
To accomplish membrane binding, 15 cm2 dishes containing 70% confluent NIH-3T3 cells are transfected with 10 μg of receptor plasmid DNA using Polyfect transfection reagent. Two days post-transfection, homogenized cells expressing the target serotonin receptor are spun down at 11,000 g for 30 minutes at 4°C while being diluted in 20 mM HEPES/10 mM EDTA. After discarding the supernatant, the pellet is spun down again while resuspended in 20 mM HEPES/1 mM EDTA. Membranes are used for binding assays after the pellet has been resuspended in a solution of 20 mM HEPES/0.5 mM EDTA.
To ascertain total membrane protein, Bradford analysis is utilized. 12-point concentration experiments were used to derive Kd and Bmax values. For the 5-HT2A receptor, 1 nM [3H]ketanserin was used, and for the 5-HT2B and 5-HT2C receptors, 3 nM [3H]mesulergine. A fixed concentration of radioligand is present while membranes are incubated for three hours at room temperature with varying test ligand concentrations. Radioactivity is measured using TopCount[1] after the suspension has been filtered as detailed below for whole-cell binding, dried, and rinsed with ice-cold buffer.
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| Cell Assay |
In order to perform whole-cell binding, 6 million human embryonic kidney 293T cells are transfected with 5 μg of plasmid DNA using Polyfect and plated in 10-cm dishes. After two days of transfection, cells are collected using 10 mM EDTA, cleaned, and then reconstituted in binding buffer (1% bovine serum albumin in 1× DMEM). Subsequently, a total of 100 μL of ligands and 5 nM radioligand ([3H]ketanserin for 5-HT2A receptors and [3H]mesulergine for 5-HT2C-INI receptors) are added to 60,000 cells transfected with the 5-HT2A receptor or 20,000 cells transfected with the 5-HT2C-INI receptor, and they are incubated for three hours at 37°C. With a Filtermate 196 harvester, cells are filtered onto a 96-well GF/B filter plate and then rinsed with 300 mL of wash buffer (25 mM HEPES, 1 mM CaCl2, 5 mM MgCl2, and 0.25 M NaCl). Prior to adding 50 μL of scintillation fluid to each well, the filter plates are dried under a heat lamp. Using a TopCount, plates are counted. In a separate procedure, MDS Pharma Services assesses the activity of pimavanserin (10 μM) in hydrochloride salt form using a wide range of radioligand binding tests at 65 distinct receptors[1].
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| Animal Protocol |
Mice: For studies on locomotor activity, non-Swiss albino mice are employed. Pimavanserin is administered alone (s.c. 60 min before session start or p.o. 60 min before session start) to determine spontaneous activity. In trials involving hyperactivity, mice receive 0.3 mg/kg MK-801 (i.p.) 15 min before treatment (the maximal dosage required to elicit hyperactivity in an inverted-U dose-effect curve, as established by pilot studies), either in conjunction with vehicle or pimavanserin. Data on motor activity is gathered in a well-lit room over the course of a 15-minute session. The mice had never before been in contact with the motor cages. The mice are held by the base of their tails and their forepaws are placed in contact with a horizontal wire to assess the effects of myorelaxation/ataxia prior to their placement in the locomotor chambers. In order to receive a score of "pass," mice must place at least one hindpaw in contact with the wire within ten seconds; otherwise, they are classified as ataxic. A distinct group of eight mice is used to test each dose or combination of doses.
Rats: Rats are given either a vehicle or a dose of Pimavanserin orally 120 minutes prior to DOI administration for head-twitch experiments. Docusate Ic (2.5 mg/kg i.p.) is given right before the observation. Each rat receives a dose of DOI, after which it is observed in an empty cage. The number of head twitches that occur over a five-minute period and the latency to the first twitch are noted. Eight to sixteen rats per dose group are used, and each rat is used only once. |
| References |
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| Molecular Formula |
C25H34FN3O2
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|---|---|
| Molecular Weight |
427.56
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| Exact Mass |
427.26
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| Elemental Analysis |
C, 70.23; H, 8.02; F, 4.44; N, 9.83; O, 7.48
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| CAS # |
706779-91-1
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| Related CAS # |
Pimavanserin hemitartrate; 706782-28-7
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| Appearance |
Solid powder
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| SMILES |
CC(C)COC1=CC=C(C=C1)CNC(=O)N(CC2=CC=C(C=C2)F)C3CCN(CC3)C
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| InChi Key |
RKEWSXXUOLRFBX-UHFFFAOYSA-N
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| InChi Code |
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)
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| Chemical Name |
1-[(4-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-[[4-(2-methylpropoxy)phenyl]methyl]urea
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| Synonyms |
ACP-103; BVF-036; ACP 103; BVF036; ACP103; Trade name: Nuplazid
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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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.85 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 (5.85 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.85 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3389 mL | 11.6943 mL | 23.3885 mL | |
| 5 mM | 0.4678 mL | 2.3389 mL | 4.6777 mL | |
| 10 mM | 0.2339 mL | 1.1694 mL | 2.3389 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03623321 | Active Recruiting |
Drug: Pimavanserin | Neuropsychiatric Symptoms Related to Neurodegenerative Disease |
ACADIA Pharmaceuticals Inc. | July 17, 2018 | Phase 3 |
| NCT04531982 | Active Recruiting |
Drug: Pimavanserin Drug: Placebo |
Schizophrenia | ACADIA Pharmaceuticals Inc. | August 5, 2020 | Phase 3 |
| NCT05441280 | Recruiting | Drug: pimavanserin Other: Placebo |
Post-traumatic Stress Disorder Insomnia |
VA Office of Research and Development |
June 26, 2023 | Phase 2 |
| NCT04373317 | Recruiting | Drug: Pimavanserin Drug: Quetiapine |
Parkinson's Disease Psychosis | VA Office of Research and Development |
October 24, 2022 | Phase 4 |
| NCT06068465 | Recruiting | Drug: pimavanserin tartrate Drug: Placebo |
Parkinson's Disease Psychosis | Tasly Pharmaceutical Group Co., Ltd |
September 27, 2023 | Phase 3 |
Anti-tremor effect of ACP-103. The number of tremulous jaw movements is shown as a function of ACP-103 dose in combination with tacrine.Pharmacol Biochem Behav.2008 Oct;90(4):540-4. |
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Anti-dyskinetic effect of ACP-103. Dyskinesia severity score is shown as a function of ACP-103 dose in combination with levodopa in MPTP-treated monkeys.Pharmacol Biochem Behav.2008 Oct;90(4):540-4. |
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