5-HT2A ( pIC50 = 8.7 )
Pimavanserin tartrate targets human 5-HT2A receptor (inverse agonist; pKi = 9.3 ± 0.14 in membrane binding, Ki = 0.5 nM; pKi = 9.70 ± 0.19 in whole-cell binding, Ki = 0.20 nM; pIC50 = 8.73 ± 0.39 in R-SAT functional assay, IC50 = 1.86 nM; inverse agonistic efficacy 93 ± 6% relative to ritanerin) [1].
Also targets human 5-HT2C receptor (pKi = 8.80 ± 0.07 in membrane binding, Ki = 1.58 nM; pKi = 8.00 ± 0.14 in whole-cell binding, Ki = 10 nM; pIC50 = 7.04 ± 0.15 in R-SAT, IC50 = 91.2 nM; efficacy 110 ± 3%) [1].
No significant activity at 5-HT2B, dopamine D2, or 31 other human monoaminergic receptors (pEC50 or pKi < 6.0) [1].
Broad screen radioligand binding: at 10 μM, showed 100% inhibition at serotonin 5-HT2A (IC50 0.46 nM, Ki 0.13 nM), 101% at calcium channel type L (benzothiazepine site, IC50 0.34 μM, Ki 0.31 μM), 88% at calcium channel type L (dihydropyridine), 64% at adrenergic norepinephrine transporter, 60% at dopamine D3, 87% at muscarinic M1, 69% at M2, 68% at M3, 67% at sigma σ1, 75% at sigma σ2, 103% at sodium channel site 2 (IC50 1.41 μM, Ki 1.29 μM). No significant inhibition (<50%) at 54 other targets including adenosine, adrenergic α, bradykinin, dopamine D1/D2L/D4.2, endothelin, GABA, glutamate, histamine, neuropeptide Y, nicotinic acetylcholine, opiate, etc. [1]

Pimavanserin hemitartrate competitively antagonizes the binding of [3H]ketanserin to heterologously expressed human 5-HT 2A receptors with an average pKi of 9.3 in membranes and 9.70 in whole cells. Pimavanserin hemitartrate demonstrated potent inverse agonist activity in a cell-based functional assay Receptor Selection and Ascending Technology (R-SAT) with an average pIC50 of 8.7. Pimavanserin hemitartrate exhibits low affinity (average pKi 8.80 in membranes and 8.00 in whole cells, determined by binding to ligand) and potency as an inverse agonist (average pIC50 7.1 in R-SAT) against human 5 -HT 2C absorption, lacks affinity and functional activity for 5-HT 2B absorption, dopamine D2 absorption and other human monoaminergic absorption [1].

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Pimavanserin tartrate displayed potent inverse agonist activity at human 5-HT2A receptors in R-SAT functional assays with mean pIC50 of 8.73 ± 0.39 and full efficacy (93 ± 6% relative to ritanerin). It competitively antagonized serotonin-induced 5-HT2A receptor agonist responses. At 5-HT2C receptors, it showed inverse agonist activity with pIC50 7.04 ± 0.15 and efficacy 110 ± 3%, and competitively antagonized serotonin-induced responses. It lacked functional activity (pEC50 or pKi < 6.0) at 5-HT2B, dopamine D2, and 31 other human monoaminergic receptors (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F, 5-HT3, 5-HT6A, 5-HT7A, somatostatin SST1-5, etc.) when tested as agonist, inverse agonist, or competitive antagonist in R-SAT or other functional assays. [1]
Radioligand binding assays showed high affinity for 5-HT2A (membrane pKi 9.3, whole-cell pKi 9.70) and 5-HT2C (membrane pKi 8.80, whole-cell pKi 8.00). It lacked affinity (pKi < 6.0) for human dopamine D2 receptor. Broad receptor profiling (65 assays) confirmed that the only high-affinity (pKi >7.0) interactions were at 5-HT2 receptors, with additional moderate affinity at calcium channels, sigma receptors, muscarinic M1/M2/M3, sodium channel, and norepinephrine transporter. [1]

Pimavanserin (3 mg/kg, p.o.) attenuates head twitches caused by DOI in rats. Pimavanserin (3 mg/kg, p.o.) significantly reduces the hyperactivity induced by MK-801 in mice. [1] Pimavanserin (40 mg/kg, i.p.) significantly reduces tacrine-induced tremulous jaw movements in a rat model of parkinsonian tremor. [2]
Pimavanserin tartrate (3 mg/kg p.o., 2 h pretreatment) significantly attenuated DOI (2.5 mg/kg i.p.)-induced head twitches in rats: number of head twitches reduced from 5.2 ± 0.9 (vehicle) to 0.75 ± 0.27; latency increased to 264.9 ± 11.4 s. No effect on head-twitch behavior when given alone. [1]
In rats, Pimavanserin tartrate (1.0, 3.0, 10.0 mg/kg s.c., 30 min pretreatment) reversed DOI (0.5 mg/kg s.c.)-induced prepulse inhibition (PPI) deficits of acoustic startle response. DOI disrupted PPI, and ACP-103 restored PPI even at the lowest dose tested (1 mg/kg). ACP-103 did not affect basal startle response or PPI on its own. The positive control MDL-100,151 (1.0 mg/kg s.c.) also reversed DOI-induced PPI disruption. [1]
In mice, Pimavanserin tartrate (0.1 and 0.3 mg/kg s.c.; 3 mg/kg p.o.) attenuated hyperactivity induced by the NMDA antagonist MK-801 (0.3 mg/kg i.p.). It also decreased spontaneous locomotor behavior after s.c. administration but did not reduce spontaneous locomotion at efficacious doses after oral administration. No myorelaxant or ataxic effects were observed in mice as measured by the horizontal wire test. [1]

The receptor selection and amplification technology (R-SAT) assay was used to assess inverse agonist potency and efficacy. NIH-3T3 cells were grown to 80% confluence in DMEM supplemented with 10% bovine calf serum and 1% penicillin/streptomycin/glutamine. Cells were transfected in roller bottles for 18 h with the relevant G protein-coupled receptor gene and the β-galactosidase gene. After transfection, cells were trypsinized, harvested, and frozen. Aliquots were thawed and tested for response to reference agonists and inverse agonists. To initiate the assay, cells were thawed rapidly and prepared in DMEM containing 0.4% calf serum, 30% UltraCulture, and 1% penicillin/streptomycin/glutamine, then added to half-area 96-well plates containing test compounds or reference ligands. After 5 days in culture, media were removed, and cells were incubated at room temperature in phosphate-buffered saline (pH 7.4) with 3.5 mM o-nitrophenyl-β-D-galactopyranoside and 0.5% Nonidet P-40 for 2-4 h. Plates were read at 420 nm. Inverse agonist potencies are reported as pIC50 values, and efficacies as percentage inhibition relative to ritanerin (100%). [1]
For radioligand binding in membranes, NIH-3T3 cells were grown to 70% confluence in 15-cm² dishes and transfected with 10 μg of receptor plasmid DNA. Two days post-transfection, cells expressing the desired serotonin receptor were homogenized in 20 mM HEPES/10 mM EDTA and centrifuged at 11,000g at 4°C for 30 min. The pellet was resuspended in 20 mM HEPES/1 mM EDTA and centrifuged again, then resuspended in 20 mM HEPES/0.5 mM EDTA. Bradford analysis determined total membrane protein. Kd and Bmax values were derived from 12-point concentration experiments using 1 nM [3H]ketanserin for 5-HT2A or 3 nM [3H]mesulergine for 5-HT2B/2C. Membranes were incubated at room temperature for 3 h with various concentrations of test ligand and a fixed concentration of radioligand. The suspension was filtered, washed with ice-cold buffer, dried, and radioactivity determined. [1]
For whole-cell binding, 6 million HEK293T cells were plated in 10-cm dishes and transfected with 5 μg of plasmid DNA. Two days post-transfection, cells were harvested with 10 mM EDTA, washed, and resuspended in binding buffer (1× DMEM with 0.1% bovine serum albumin). Then 60,000 cells (5-HT2A) or 20,000 cells (5-HT2C-INI) were incubated at 37°C for 3 h with 5 nM radioligand ([3H]ketanserin or [3H]mesulergine) and varying ligand concentrations (total volume 100 μl in 96-well plates). Cells were filtered onto a 96-well GF/B filter plate, washed with wash buffer (25 mM HEPES, 1 mM CaCl2, 5 mM MgCl2, 0.25 M NaCl), dried, scintillation fluid added, and counted. [1]
A broad radioligand binding screen at 65 different receptors, channels, and enzymes was conducted using 10 μM Pimavanserin tartrate (hydrochloride salt). Percent inhibition was measured; for targets with >50% inhibition, IC50 and Ki were determined. [1]

Pimavanserin tartrate was evaluated in cell-based R-SAT assays using NIH-3T3 cells transiently expressing human 5-HT2A, 5-HT2B, or 5-HT2C receptors. Cells were transfected with receptor and β-galactosidase genes, then plated in 96-well plates with test compounds. After 5 days, β-galactosidase activity was measured colorimetrically to quantify receptor-mediated responses. The assay detects constitutive activity, allowing determination of inverse agonist potency (pIC50) and efficacy relative to ritanerin. [1]
Whole-cell radioligand binding assays were performed using HEK293T cells transiently expressing human 5-HT2A or 5-HT2C-INI receptors. Cells (60,000 for 5-HT2A; 20,000 for 5-HT2C) were incubated with 5 nM [3H]ketanserin or [3H]mesulergine and varying concentrations of test ligand at 37°C for 3 h. Bound radioactivity was measured after filtration and washing. [1]

Male Sprague-Dawley rats
3 mg/kg
p.o.

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For DOI-induced head-twitch experiments: Male Sprague-Dawley rats received vehicle or Pimavanserin tartrate orally at various doses (0.3, 1, 3, 10 mg/kg) 120 min before DOI administration (2.5 mg/kg i.p.). Immediately after DOI injection, each rat was placed into an empty cage and observed. Latency to first head twitch and number of head twitches over 5 min were recorded. Each rat used once, with 8-16 rats per dose. [1]
For prepulse inhibition (PPI) experiments: Rats were matched for baseline startle magnitude and PPI. After 2 days, rats were pretreated with saline (s.c.), MDL-100,151 (1.0 mg/kg s.c.), or Pimavanserin tartrate (1.0, 3.0, 10.0 mg/kg s.c.) 30 min before being placed in startle chambers. Five minutes after pretreatment, rats received either DOI HCl (0.5 mg/kg s.c.) or 0.9% saline. The acoustic startle session lasted ~37 min, with 62 acoustic trials (24 pulse-alone 120-dB, 10 each of prepulse intensities 68/71/77 dB followed by pulse, 8 no-stimulus) and then 100 air puff trials. Startle magnitude and %PPI were calculated. A crossover design was used after 1 week. [1]
For locomotor activity experiments: Non-Swiss albino mice were used. For spontaneous activity, Pimavanserin tartrate was administered alone (s.c. 60 min presession or p.o. 60 min presession). For hyperactivity, mice were treated with MK-801 (0.3 mg/kg i.p.) 15 min presession in combination with vehicle or ACP-103. Motor activity was collected during a 15-min session in a lit room. Immediately before locomotor testing, myorelaxation/ataxia was assessed by placing the mouse’s forepaws on a horizontal wire; failure to bring at least one hindpaw to the wire within 10 s was scored as ataxic. Each dose/dose combination tested in separate groups (n=8). [1]

Pimavanserin tartrate demonstrated >42.6% oral bioavailability in male Sprague-Dawley rats (weight 280-310 g). For intravenous administration, blood samples were withdrawn at 0 (predose), 2, 5, 30, 60, 120, 240, 360, and 480 min. For oral administration, samples at 0, 5, 30, 60, 120, 240, 360, and 480 min. Whole blood (0.50-0.75 ml) was collected via jugular venipuncture into heparinized tubes, placed on ice, centrifuged, and plasma frozen at -70°C. Plasma concentrations were determined by LC-MS/MS after protein precipitation with acetonitrile and internal standard. Noncompartmental analysis was performed using WinNonlin. High volume of distribution and high clearance were also observed. [1]

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no information on the clinical use of pimovaserin during lactation. If a mother needs to use pimovaserin, she should not discontinue breastfeeding. However, especially when breastfeeding newborns or premature infants, other medications should be preferred. ◉ Effects on Breastfed Infants
No published information found as of the revision date. ◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.

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In behavioral studies, Pimavanserin tartrate did not exhibit myorelaxant or ataxic effects in mice as measured by the horizontal wire test at doses that attenuated MK-801-induced hyperactivity. It did not reduce spontaneous locomotion at efficacious doses after oral administration, although it did decrease spontaneous locomotor behavior after subcutaneous administration. No effect on basal startle response or PPI on its own was observed. These results suggest less sedation compared to other antipsychotics. No overt toxicity or mortality was reported. [1]

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

[2]. Pharmacol Biochem Behav . 2008 Oct;90(4):540-4.

Pemovanserine tartrate is the hemitartrate salt of pimova serine, belonging to the tartrate salt class. It is an atypical antipsychotic drug used to treat hallucinations and delusions associated with Parkinson's disease. It has antipsychotic, serotonergic antagonist, and serotonin 2A receptor inverse agonist effects. It contains the pimova serine (1+) domain.
See also: pimova serine (containing the active moiety).

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Pimavanserin tartrate is a selective 5-HT2A receptor inverse agonist that lacks significant affinity for dopamine D2 receptors, distinguishing it from typical antipsychotics. It is hypothesized to mediate antipsychotic efficacy via 5-HT2A inverse agonism without causing extrapyramidal motor side effects or tardive dyskinesia associated with D2 antagonism. The compound shows potential for treating psychosis in Parkinson's disease (where D2 antagonists are contraindicated) as well as schizophrenia. Clinical data with other 5-HT2A-selective compounds (M100907, eplivanserin) suggest efficacy in acute schizophrenia. ACP-103 may also be useful as combination therapy with existing antipsychotics. [1]

C54H74F2N6O10

1005.21

1004.54

C, 64.52; H, 7.42; F, 3.78; N, 8.36; O, 15.92

706782-28-7

Pimavanserin; 706779-91-1

11672491

White to off-white solid powder

7.868

6

14

19

72

657

2

O=C(NCC1=CC=C(OCC(C)C)C=C1)N(CC2=CC=C(F)C=C2)C3CCN(C)CC3.O=C(O)[C@H](O)[C@@H](O)C(O)=O.O=C(NCC4=CC=C(OCC(C)C)C=C4)N(CC5=CC=C(F)C=C5)C6CCN(C)CC6

RGSULKHNAKTFIZ-CEAXSRTFSA-N

InChI=1S/2C25H34FN3O2.C4H6O6/c2*1-19(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;5-1(3(7)8)2(6)4(9)10/h2*4-11,19,23H,12-18H2,1-3H3,(H,27,30);1-2,5-6H,(H,7,8)(H,9,10)/t;;1-,2-/m..1/s1

(2R,3R)-2,3-dihydroxybutanedioic acid;1-[(4-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-[[4-(2-methylpropoxy)phenyl]methyl]urea

ACP-103 tartrate; ACP 103; BVF036; ACP-103; BVF-036; 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

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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: ≥ 2.08 mg/mL (4.14 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 20.8 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: ≥ 2.08 mg/mL (4.14 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 20.8 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: ≥ 2.08 mg/mL (4.14 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 20.8 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.)