"目录号: HY-14557
GPCR/G ProteinNeuronal Signaling-
Pimavanserin 是一种有效的5-hydroxytryptamine (5-HT)2A受体反向激动剂，在细胞功能测定受体选择和扩增技术 (R-SAT) 中，具有有效的反向激动剂活性，平均pIC50为 8.7。
5-HT Receptor
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生物活性
Description
Pimavanserin is a potent5-hydroxytryptamine (5-HT)2Areceptor inverse agonist, displays potent inverse agonist activity in the cell-based functional assay receptor selection and amplification technology (R-SAT), with a meanpIC50of 8.7.
IC50& Target
pIC50: 8.7 (5-HT2A)[1]
In Vitro
Pimavanserin (ACP-103) competitively antagonizes the binding of [3H]ketanserin to heterologously expressed human 5-HT2Areceptors with a mean pKiof 9.3 in membranes and 9.70 in whole cells. Pimavanserin demonstrates lesser affinity (mean pKiof 8.80 in membranes and 8.00 in whole cells, as determined by radioligand binding) and potency as an inverse agonist (mean pIC507.1 in R-SAT) at human 5-HT2Creceptors, and lacked affinity and functional activity at 5-HT2Breceptors, dopamine D2receptors, and other human monoaminergic receptors[1]. Pimavanserin (ACP-103) is highly selective for 5-HT2Areceptors, 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-HT2Areceptors over 5-HT2Creceptors depending on the assay[2].
In Vivo
Pimavanserin (ACP-103) is a potent, efficacious, orally active 5-HT2Areceptor 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-HT2Areceptor 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-HT2Areceptor mechanism of action in vivo and antipsychotic-like efficacy. Pimavanserin demonstrates >42.6% oral bioavailability in rats[1].
Clinical Trial
NCT00550238
ACADIA Pharmaceuticals Inc.
Parkinson's Disease Psychosis
July 2007
Phase 3
NCT00361166
ACADIA Pharmaceuticals Inc.
Schizophrenia
August 2005
Phase 2
NCT00477672
ACADIA Pharmaceuticals Inc.
Parkinson's Disease Psychosis
June 2007
Phase 3
NCT00087542
ACADIA Pharmaceuticals Inc.
Hallucinations-Psychoses-Parkinson's Disease
March 2004
Phase 2
NCT00658567
ACADIA Pharmaceuticals Inc.
Parkinson's Disease Psychosis
March 2008
Phase 3
NCT01518309
ACADIA Pharmaceuticals Inc.
Parkinson's Disease Psychosis
November 2004
Phase 2
NCT00086294
National Institute of Neurological Disorders and Stroke (NINDS)-National Institutes of Health Clinical Center (CC)
Parkinson's Disease-Dyskinesias
June 25, 2004
Phase 2
NCT00550238
ACADIA Pharmaceuticals Inc.
Parkinson's Disease Psychosis
July 2007
Phase 3
NCT00361166
ACADIA Pharmaceuticals Inc.
Schizophrenia
August 2005
Phase 2
NCT00477672
ACADIA Pharmaceuticals Inc.
Parkinson's Disease Psychosis
June 2007
Phase 3
NCT00087542
ACADIA Pharmaceuticals Inc.
Hallucinations-Psychoses-Parkinson's Disease
March 2004
Phase 2
NCT00658567
ACADIA Pharmaceuticals Inc.
Parkinson's Disease Psychosis
March 2008
Phase 3
NCT01518309
ACADIA Pharmaceuticals Inc.
Parkinson's Disease Psychosis
November 2004
Phase 2
NCT00086294
National Institute of Neurological Disorders and Stroke (NINDS)-National Institutes of Health Clinical Center (CC)
Parkinson's Disease-Dyskinesias
June 25, 2004
Phase 2
NCT03121586
ACADIA Pharmaceuticals Inc.
Schizophrenia
December 2016
Phase 3
NCT03118947
ACADIA Pharmaceuticals Inc.
Agitation and Aggression in Alzheimer's Disease
February 23, 2017
Phase 2
NCT02035553
ACADIA Pharmaceuticals Inc.
Alzheimer's Disease Psychosis
November 2013
Phase 2
NCT01174004
ACADIA Pharmaceuticals Inc.
Parkinson's Disease Psychosis
July 2010
Phase 3
NCT02970292
ACADIA Pharmaceuticals Inc.
Schizophrenia
October 2016
Phase 3
NCT02970305
ACADIA Pharmaceuticals Inc.
Schizophrenia
November 2016
Phase 2
NCT03018340
ACADIA Pharmaceuticals Inc.
Adjunctive Treatment of Major Depressive Disorder
December 2016
Phase 2
NCT02992132
ACADIA Pharmaceuticals Inc.
Agitation and Aggression in Alzheimer's Disease
November 2016
Phase 2
NCT02762591
ACADIA Pharmaceuticals Inc.
Parkinson's Disease Psychosis
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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.