Pimavanserin displays nanomolar potency as a 5-HT2A receptor inverse agonist, selectivity for 5-HT2A over 5-HT2C receptors, and no meaningful activity at any other G-protein coupled receptor. Pimavanserin demonstrates robust activity in preclinical models of schizophrenia and PDP, and do not worsen motoric symptoms, in contrast to the APDs tested. Pimavanserin showes highly significant benefits in the primary endpoint, the scale for assessment of positive symptoms-PD, a scale adapted for use in PDP. Pimavanserin is safe and well-tolerated with long-term use.
|Cell lines||NIH-3T3 cells|
|Preparation method||Receptor Selection and Amplification Technology.
In brief, NIH-3T3 cells were grown to 80% confluence in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% bovine calf serum (Hyclone Laboratories, Logan, UT) and 1% penicillin/streptomycin/glutamine (Invitrogen, Carlsbad, CA). Cells were transfected in roller bottles for 18 h with the relevant G protein-coupled receptor gene and the gene for β-galactosidase. After transfection, cells were trypsinized, harvested, and frozen. Aliquots of frozen cell batches were thawed and tested for response to reference agonists and inverse agonists ensuring pharmacologically appropriate responses. To initiate an assay, cells were thawed rapidly and prepared in DMEM contained 0.4% calf serum (Hyclone Laboratories), 30% UltraCulture (BioWhittaker, Rockland, ME), and 1% penicillin/streptomycin/glutamine, and then they were added to half-area 96-well microtiter plates containing either test compounds or reference ligands. After 5 days in culture, media were removed from the wells, and the cells were incubated at room temperature in 200 μl of phosphate-buffered saline, pH 7.4, with 3.5 mM o-nitrophenyl-β-d-galactopyranoside (Sigma-Aldrich, St. Louis, MO) and 0.5% Nonidet P-40 (Sigma-Aldrich). After 2 to 4 h, the plates were read at 420 nm on a plate-reader (Bio-Tek Instruments, Winooski, VT).
|Incubation time||5 days|
|Animal models||DOI head-twitch experiments in rats and Non-Swiss albino mice|
|Dosages||1, 3 or 10 mg/kg|
|Administration||s.c. or p.o.|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Source||Neurochem Res (2014). Figure 3. Pimavanserin|
|Cell Lines||animals with bilateral lesions of the SN|
|Incubation Time||24 h|
|Results||Notably, pimavanserin not only reversed the psychosis-like behaviors, but did so without augmenting motor problems or blocking the ability of L-DOPA to improve motor behavior|
|Source||Neurochem Res (2014). Figure 2. Pimavanserin|
|Cell Lines||NIH 3T3 cells|
|Results||Pimavanserin is a potent, selective 5-HT2A inverse agonist, with selectivity over 5-HT2C receptors in binding and functional assays and little to no activity at other GPCRs in contrast to the available APDs|
On the Discovery and Development of Pimavanserin: A Novel Drug Candidate for Parkinson's Psychosis.
Hacksell U, et al. Neurochem Res. 2014 Mar 30. PMID: 24682754.
Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial.
Cummings J, et al. Lancet. 2014 Feb 8;383(9916):533-40. PMID: 24183563.
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.
Vanover KE, et al. J Pharmacol Exp Ther. 2006 May;317(2):910-8. PMID: 16469866.
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