5-HT_2A Receptor ( pIC50 = 8.7 )

Pimavanserin (ACP-103) has a mean pK_i of 9.3 in membranes and 9.70 in whole cells, which competitively opposes [³H]ketanserin's binding to heterologously expressed human 5-HT_2A 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-HT_2C receptors (mean pK_i of 8.80 in membranes and 8.00 in whole cells). It also shows no affinity or functional activity at 5-HT_2B receptors, dopamine D₂ receptors, or other human monoaminergic receptors[1]. Pimavanserin (ACP-103) exhibits a strong preference for 5-HT_2A receptors and lacks affinity for other receptors in a broad profile screen that includes 65 distinct molecular targets. Pimavanserin only shows affinity for 5-HT_2C receptors, and depending on the assay, it is roughly 30-fold more selective for 5-HT_2A receptors than 5-HT_2C receptors[2].

Pimavanserin (also known as ACP-103) is a strong, effective, and orally active inverse agonist of the 5-HT_2A 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-HT_2A 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].

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 K_d and B_max values. For the 5-HT_2A receptor, 1 nM [³H]ketanserin was used, and for the 5-HT_2B and 5-HT_2C 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.

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-HT_2A receptors and [³H]mesulergine for 5-HT_2C-INI receptors) are added to 60,000 cells transfected with the 5-HT_2A receptor or 20,000 cells transfected with the 5-HT_2C-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].

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.

Absorption, Distribution and Excretion
The median Tmax of pimavanserin in clinical studies was 6 hours, regardless of the dose. The bioavailability of an oral tablet of pimavanserin and a solution were almost identical. Ingestion of a high-fat meal had no significant effect on the rate (Cmax) and extent (AUC) of pimavanserin exposure. Cmax decreased by about 9% while AUC increased by about 8% with a high-fat meal. The major active circulating N-desmethylated metabolite, AC-279, has a median Tmax of 6 hours.
Approximately 0.55% of the 34 mg oral dose of ¹⁴C-pimavanserin was eliminated as unchanged drug in urine and 1.53% was eliminated in feces after 10 days. Less than 1% of the administered dose of pimavanserin and its active metabolite AC-279 were recovered in urine.
Following administration of a single dose of 34 mg, the average apparent volume of distribution was 2173 L in clinical studies.

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Metabolism / Metabolites
Pimavanserin is mainly metabolized CYP3A4 and CYP3A5 hepatic cytochrome enzymes, and to a lesser extent by CYP2J2, CYP2D6, and other cytochrome and flavin-containing monooxygenase enzymes. CYP3A4 metabolizes pimavanserin to its major active metabolite, AC-279.

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Biological Half-Life
The average plasma half-lives for pimavanserin and its active metabolite (AC-279) are estimated at 57 hours and 200 hours, respectively.

Hepatotoxicity
Liver test abnormalities are uncommon (
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of pimavanserin during breastfeeding. If pimavanserin is required by the mother, it is not a reason to discontinue breastfeeding. However, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Pimavanserin is highly protein-bound (~95%) in human plasma. Protein binding appeared to be dose-independent and did not change significantly over dosing time from Day 1 to Day 14.

[1]. 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 inverse agonist. J Pharmacol Exp Ther. 2006 May;317(2):910-8.

[2]. 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 is a member of the class of ureas in which three of the four hydrogens are replaced by 4-fluorobenzyl, 1-methylpiperidin-4-yl, and 4-(isopropyloxy)benzyl groups. An atypical antipsychotic that is used (in the form of its tartrate salt) for treatment of hallucinations and delusions associated with Parkinson's disease. It has a role as an antipsychotic agent, a 5-hydroxytryptamine 2A receptor inverse agonist and a serotonergic antagonist. It is a member of ureas, a member of piperidines, a member of monofluorobenzenes, an aromatic ether and a tertiary amino compound. It is a conjugate base of a pimavanserin(1+).
Pimavanserin is an atypical antipsychotic indicated for the treatment of psychiatric disorders. Although the exact mechanism of action is unknown, it is thought that pimavanserin interacts with the serotonin receptors, particularly the 5-HT2A and HT2C receptors. Unlike other atypical antipsychotics, pimavanserin lacks inherent dopaminergic activity. In fact, pimavanserin is the first antipsychotic drug without D2 blocking activity. Therefore, pimavanserin can be used to treat psychotic symptoms without causing extrapyramidal or worsening motor symptoms. Pimavanserin is marketed under the trade name NUPLAZID and developed by Acadia Pharmaceuticals. It was approved by the FDA in April 2016 for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis thanks to favorable results from a pivotal six-week, randomized, placebo-controlled, parallel-group study. Pimavanserin was also under review as a potential treatment for dementia-related psychosis; however, as of April 2021, FDA approval has not been granted for this indication despite previous breakthrough designation.
Pimavanserin is an Atypical Antipsychotic.
Pimavanserin is an atypical antipsychotic used in the treatment of hallucinations and delusions in patients with Parkinson disease and psychosis. Use of pimavanserin is associated with a low rate of serum enzyme elevations during therapy but it has not been linked to instances of clinically apparent acute liver injury.
See also: Pimavanserin Tartrate (has salt form).

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Drug Indication
Pimavanserin is indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.
Treatment of schizophrenia and other psychotic disorders

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Mechanism of Action
Parkinson's disease psychosis (PDP) is an imbalance of serotonin and dopamine from disruption of the normal balance between the serotonergic and dopaminergic receptors and neurotransmitters in the brain. The mechanism by which pimavanserin treats hallucinations and delusions associated with Parkinson’s disease psychosis is not fully established. It is possible that pimavanserin acts via inverse agonist and antagonist activity at serotonin 5-HT_2A receptors with limited effects on serotonin 5-HT_2C receptors. Pimavanserin is an inverse agonist and antagonist of serotonin 5-HT_2A receptors with high binding affinity, demonstrating low binding affinity to serotonin 5-HT_2C receptors. In addition, this drug exhibits low affinity binding to sigma 1 receptors. Pimavanserin lacks activity at muscarinic, dopaminergic, adrenergic, and histaminergic receptors, preventing various undesirable effects typically associated with antipsychotics.

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Pharmacodynamics
Pimavanserin's unique actions on serotonin receptors improve symptoms of hallucinations and delusions associated with Parkinson's disease. In clinical studies, 80.5% of individuals treated with pimavanserin reported improvement in symptoms. Pimavanserin does not worsen motor functioning in patients with Parkinson's disease psychosis. In vitro, pimavanserin acts as an inverse agonist and antagonist at serotonin 5-HT_2A receptors with high binding affinity (K_i value 0.087 nM) and at serotonin 5-HT_2C receptors with lower binding affinity (K_i value 0.44 nM). Pimavanserin shows low binding to sigma 1 receptors (K_i value 120 nM) and has no appreciable affinity (K_i value >300 nM), to serotonin 5-HT_2B, dopaminergic (including D₂), muscarinic, histaminergic, or adrenergic receptors, or to calcium channels. The effect of pimavanserin on the QTc interval was evaluated in a randomized placebo- and positive-controlled double-blind, multiple-dose parallel thorough QTc study in 252 healthy subjects. A central tendency analysis of the QTc data at steady-state demonstrated that the maximum mean change from baseline (upper bound of the two-sided 90% CI) was 13.5 (16.6) msec at a dose of twice the therapeutic dose. A pharmacokinetic/pharmacodynamic analysis with pimavanserin suggested a concentration-dependent QTc interval prolongation in the therapeutic range. In the 6-week, placebo-controlled effectiveness studies, mean increases in QTc interval of ~5-8 msec were observed in patients receiving once-daily doses of pimavanserin 34 mg. These data are consistent with the profile observed in a thorough QT study in healthy subjects. Sporadic QTcF values ≥500 msec and change from baseline values ≥60 msec were observed in subjects treated with pimavanserin 34 mg; although the incidence was generally similar for pimavanserin and placebo groups. There were no reports of torsade de pointes or any differences from placebo in the incidence of other adverse reactions associated with delayed ventricular repolarization in studies of pimavanserin, including those patients with hallucinations and delusions associated with Parkinson’s disease psychosis.

C25H34FN3O2

427.56

427.263

C, 70.23; H, 8.02; F, 4.44; N, 9.83; O, 7.48

706779-91-1

Pimavanserin hemitartrate; 706782-28-7

10071196

White to off-white solid powder

1.1±0.1 g/cm3

604.2±55.0 °C at 760 mmHg

117-119

319.2±31.5 °C

0.0±1.7 mmHg at 25°C

1.576

4.67

1

4

8

31

523

0

CC(C)COC1=CC=C(CNC(N(CC2=CC=C(F)C=C2)C3CCN(C)CC3)=O)C=C1

RKEWSXXUOLRFBX-UHFFFAOYSA-N

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)

1-[(4-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-[[4-(2-methylpropoxy)phenyl]methyl]urea

ACP-103; BVF-036; ACP 103; BVF036; ACP103; Trade name: Nuplazid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

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.

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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.

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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.
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.

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 (Please use freshly prepared in vivo formulations for optimal results.)