Pimavanserin, sold under the brand name Nuplazid, is an atypical antipsychotic which is approved for the treatment of Parkinson's disease psychosis. It is taken by mouth.
Side effects of pimavanserin include peripheral edema and confusion. Unlike other antipsychotics, pimavanserin is not a dopamine receptor antagonist, but rather is a selective antagonist or inverse agonist of the serotonin 5-HT2A receptor and to a lesser extent of the serotonin 5-HT2C receptor.
Pimavanserin was first approved for medical use in 2016. It was approved as a generic medication in 2024. |
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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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C1=C(C=CC(=C1)CNC(N(C2CCN(CC2)C)CC3=CC=C(C=C3)F)=O)OCC(C)C |
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Bronsted base
A molecular entity capable of accepting a hydron from a donor (Bronsted acid).
(via organic amino compound )
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5-hydroxytryptamine 2A receptor inverse agonist
An inverse agonist that binds to the same receptor as a 5-hydroxytryptamine 2A receptor agonist, but which induces a pharmacological response opposite to that agonist.
serotonergic antagonist
Drugs that bind to but do not activate serotonin receptors, thereby blocking the actions of serotonin or serotonergic agonists.
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antipsychotic agent
Antipsychotic drugs are agents that control agitated psychotic behaviour, alleviate acute psychotic states, reduce psychotic symptoms, and exert a quieting effect.
serotonergic antagonist
Drugs that bind to but do not activate serotonin receptors, thereby blocking the actions of serotonin or serotonergic agonists.
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N-[(4-fluorophenyl)methyl]-N-(1-methylpiperidin-4-yl)-N'-{[4-(2-methylpropoxy)phenyl]methyl}urea
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N-(4-Fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide
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10386699
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Reaxys Registry Number
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Reaxys
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706779-91-1
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Traynor K (2016) Pimavanserin approved for Parkinson's-related hallucinations, delusions. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists 73, 853 [PubMed:27261226] | Stahl SM (2016) Mechanism of action of pimavanserin in Parkinson's disease psychosis: targeting serotonin 5HT2A and 5HT2C receptors. CNS spectrums 21, 271-275 [PubMed:27503570] [show Abstract] Pimavanserin, a novel agent approved for the treatment of Parkinson's disease psychosis, has potent actions as an antagonist/inverse agonist at serotonin 5HT2A receptors and less potent antagonist/inverse agonist actions at 5HT2C receptors. | Banks ML (2016) Effects of 7-day repeated treatment with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in male rhesus monkeys. Drug and alcohol dependence 165, 260-264 [PubMed:27242287] [show Abstract]
BackgroundPreclinical drug vs. food choice is an emerging group of drug self-administration procedures that have shown predictive validity to clinical drug addiction. Emerging data suggest that serotonin (5-HT)2A receptors modulate mesolimbic dopamine function, such that 5-HT2A antagonists blunt the abuse-related neurochemical effects of monoamine transporter substrates, such as amphetamine or methamphetamine. Whether subchronic 5-HT2A antagonist treatment attenuates methamphetamine reinforcement in any preclinical drug self-administration procedure is unknown. The study aim was therefore to determine 7-day treatment effects with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in monkeys.MethodsBehavior was maintained under a concurrent schedule of food delivery (1g pellets, fixed-ratio 100 schedule) and intravenous methamphetamine injections (0-0.32 mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n=3). Methamphetamine choice dose-effect functions were determined daily before and during 7-day repeated pimavanserin (1.0-10mg/kg/day, intramuscular) treatment periods.ResultsUnder control conditions, increasing methamphetamine doses resulted in a corresponding increase in methamphetamine vs. food choice. Repeated pimavanserin administration failed to attenuate methamphetamine choice and produce a reciprocal increase in food choice in any monkey up to doses (3.2-10mg/kg) that suppressed rates of operant responding primarily during components where behavior was maintained by food pellets.ConclusionsRepeated 5-HT2A receptor inverse agonist/antagonist treatment did not attenuate methamphetamine reinforcement under a concurrent schedule of intravenous methamphetamine and food presentation in nonhuman primates. Overall, these results do not support the therapeutic potential of 5-HT2A inverse agonists/antagonists as candidate medications for methamphetamine addiction. | Markham A (2016) Pimavanserin: First Global Approval. Drugs 76, 1053-1057 [PubMed:27262680] [show Abstract] Pimavanserin (Nuplazid™) is a selective and potent serotonin 2A (5-HT2A) receptor inverse agonist and antagonist developed by ACADIA Pharmaceuticals that has been approved in the US as a treatment for patients with hallucinations and delusions associated with Parkinson's disease psychosis. Up to 60 % of patients with Parkinson's disease may develop Parkinson's disease psychosis, which is associated with increased morbidity and mortality and has few treatment options. This article summarizes the milestones in the development of pimavanserin leading to this first approval for the treatment of hallucinations and delusions in patients with Parkinson's disease psychosis. | Hermanowicz S, Hermanowicz N (2016) The safety, tolerability and efficacy of pimavanserin tartrate in the treatment of psychosis in Parkinson's disease. Expert review of neurotherapeutics 16, 625-633 [PubMed:26908168] [show Abstract] Parkinson's disease psychosis (PDP) is a common and often very disturbing component of Parkinson's disease (PD). PDP consists of hallucinations that are mainly visual and delusions that are often of a paranoid nature. These symptoms can be the most troubling and disruptive of all the manifestations of Parkinson's disease. Current treatment methods include the reduction of anti-Parkinson's medications, a strategy that may worsen the motor problems the medications are prescribed to alleviate, and the introduction of selected antipsychotic medications that carry with them the potential for troubling side effects and serious consequences. Pimavanserin has been developed and studied in clinical trials to specifically address Parkinson's disease psychosis and has been submitted to the U.S. Food and Drug Administration for its approval for this purpose. If this is granted, we believe the evidence of Pimavanserin efficacy, safety and tolerability will position this medication as the first choice for treatment of Parkinson's disease psychosis. | Howland RH (2016) Pimavanserin: An Inverse Agonist Antipsychotic Drug. Journal of psychosocial nursing and mental health services 54, 21-24 [PubMed:27245248] [show Abstract] Approximately all clinically useful antipsychotic drugs have known activity as dopamine receptor antagonists, but many of these drugs also are inverse agonists at the serotonin-2A (5HT2A) receptor. Pimavanserin is an inverse agonist at the 5HT2A receptor, with a lower binding affinity at the serotonin-2C receptor and sigma 1 receptor, but no significant binding to dopamine or other receptors. Because of its unique pharmacology, pimavanserin was approved for the treatment of psychosis associated with Parkinson's disease, and it has a low risk for exacerbating motor symptoms compared to standard antipsychotic medications. Whether pimavanserin can treat psychotic symptoms in schizophrenia, psychotic depression, psychotic mania, delirium, or drug-induced psychosis, is not known. Based on its inverse agonist effect at 5HT2A receptors, pimavanserin may have potential for treating symptoms associated with the use of hallucinogen drugs and for treating akathisia associated with antipsychotic medications. [Journal of Psychosocial Nursing and Mental Health Services, 54 (6), 21-24.]. | (2016) Pimavanserin (Nuplazid) for Parkinson's disease psychosis. The Medical letter on drugs and therapeutics 58, 74-75 [PubMed:27249096] | Andersen VL, Hansen HD, Herth MM, Dyssegaard A, Knudsen GM, Kristensen JL (2015) (11)C-labeling and preliminary evaluation of pimavanserin as a 5-HT2A receptor PET-radioligand. Bioorganic & medicinal chemistry letters 25, 1053-1056 [PubMed:25655720] [show Abstract] Pimavanserin is a selective serotonin 2A receptor (5-HT2AR) inverse agonist that has shown promise for treatment of psychotic symptoms in patients with Parkinson's disease. Here, we detail the (11)C-labeling and subsequently evaluate pimavanserin as a PET-radioligand in pigs. [(11)C]Pimavanserin was obtained by N-methylation of an appropriate precursor using [(11)C]MeOTf in acetone at 60°C giving radiochemical yields in the range of 1-1.7GBq (n=4). In Danish Landrace pigs the radio ligand readily entered the brain and displayed binding in the cortex in accordance with the distribution of 5-HT2ARs. However, this binding could not be blocked by either ketanserin or pimavanserin itself, indicating high nonspecific binding. The lack of displacement by the 5-HT2R antagonist and binding in the thalamus suggests that [(11)C]pimavanserin is not selective for the 5-HT2AR in pigs. | Hunter NS, Anderson KC, Cox A (2015) Pimavanserin. Drugs of today (Barcelona, Spain : 1998) 51, 645-652 [PubMed:26744739] [show Abstract] Pimavanserin (ACP-103) is a selective inverse agonist of the 5-hydroxytryptamine 2A (5-HT2A) receptor intended to treat patients with Parkinson's disease psychosis (PDP). Currently there are no FDA-approved medications in the United States for the treatment of PDP, although on September 2, 2014, the United States Food and Drug Administration granted breakthrough therapy status to pimavanserin, highlighting the unmet need for therapeutics in this class. Most antipsychotic medications worsen motor dysfunction due to dopamine antagonism, and all carry a black box warning for an increased risk of mortality in elderly patients with dementia-related psychosis. Data from phase II and phase III clinical trials suggest that pimavanserin is a safe and effective treatment option for PDP. Trial results indicate a significant reduction in hallucinations and delusions in patients with PDP without worsening motor symptoms. Additional studies are ongoing for the treatment of Alzheimer's psychosis, schizophrenia and insomnia. Such promising outcomes warrant a review of the available literature regarding pimavanserin and its use in the treatment of PDP symptoms. | Cummings J, Isaacson S, Mills R, Williams H, Chi-Burris K, Corbett A, Dhall R, Ballard C (2014) Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet (London, England) 383, 533-540 [PubMed:24183563] [show Abstract]
BackgroundParkinson's disease psychosis, which includes hallucinations and delusions, is frequent and debilitating in people with Parkinson's disease. We aimed to assess safety and efficacy of pimavanserin, a selective serotonin 5-HT2A inverse agonist, in this population.MethodsIn our 6 week, randomised, double-blind, placebo-controlled study, we enrolled adults (aged ≥40 years) with Parkinson's disease psychosis. Antipsychotic treatments were not permitted during the study, but controlled antiparkinsonian medication or deep brain stimulation was allowed. Eligible participants entered a 2 week non-pharmacological lead-in phase to limit the placebo response, after which they were randomly allocated (1:1) to receive pimavanserin 40 mg per day or matched placebo. The primary outcome was antipsychotic benefit as assessed by central, independent raters with the Parkinson's disease-adapted scale for assessment of positive symptoms (SAPS-PD) in all patients who received at least one dose of study drug and had a SAPS assessment at baseline and at least one follow-up. We assessed safety and tolerability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01174004.FindingsBetween Aug 11, 2010, and Aug 29, 2012, we randomly allocated 199 patients to treatment groups. For 90 recipients of placebo and 95 recipients of pimavanserin included in the primary analysis, pimavanserin was associated with a -5·79 decrease in SAPS-PD scores compared with -2·73 for placebo (difference -3·06, 95% CI -4·91 to -1·20; p=0·001; Cohen's d 0·50). Ten patients in the pimavanserin group discontinued because of an adverse event (four due to psychotic disorder or hallucination within 10 days of start of the study drug) compared with two in the placebo group. Overall, pimavanserin was well tolerated with no significant safety concerns or worsening of motor function.InterpretationPimavanserin may benefit patients with Parkinson's disease psychosis for whom few other treatment options exist. The trial design used in this study to manage placebo response could have applicability to other studies in neuropsychiatric disease.FundingACADIA Pharmaceuticals. | Fox SH (2014) Pimavanserin as treatment for Parkinson's disease psychosis. Lancet (London, England) 383, 494-496 [PubMed:24183566] | Hacksell U, Burstein ES, McFarland K, Mills RG, Williams H (2014) On the discovery and development of pimavanserin: a novel drug candidate for Parkinson's psychosis. Neurochemical research 39, 2008-2017 [PubMed:24682754] [show Abstract] Parkinson's disease psychosis (PDP) is a condition that may develop in up to 60 % of Parkinson's patients, and is a major reason for nursing home placement for those affected. There are no FDA approved drugs for PDP but low doses of atypical anti-psychotic drugs (APDs) are commonly prescribed off-label. Only low-dose clozapine has shown efficacy in randomized controlled trials, but all APDs have black box warnings related to the increased mortality and morbidity when used in elderly demented patients. Using molecular pharmacological profiling of a large collection of marketed drugs, we discovered that potent inverse agonist activity against 5-HT2A serotonin receptors was a common feature of atypical APDs, especially the atypical APDs used to treat PDP. Since low-dose clozapine therapy selectively blocks this receptor, it was hypothesized that a highly selective 5-HT2A receptor inverse agonist might provide good symptom control in patients suffering from PDP, with a greatly improved safety and tolerability profile. A high throughput screening and subsequent chemical lead optimization campaign to develop potent, selective 5-HT2A receptor inverse agonists was launched, eventually resulting in the discovery of pimavanserin. 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. It demonstrated robust activity in preclinical models of schizophrenia and PDP, and did not worsen motoric symptoms, in contrast to the APDs tested. In a Phase III clinical trial, pimavanserin showed highly significant benefits in the primary endpoint, the scale for assessment of positive symptoms-PD, a scale adapted for use in PDP. In addition, improvements in all other efficacy endpoints, including physician's clinical global impression, caregiver burden, night-time sleep quality and daytime wakefulness, were seen. Pimavanserin demonstrated good safety and tolerability and did not worsen motoric symptoms as assessed by the unified Parkinson's disease rating scale parts II and III. An open-label extension study has further demonstrated that pimavanserin is safe and well-tolerated with long-term use. Pimavanserin may therefore offer a viable treatment option for patients suffering from PDP. | Hubbard D, Hacksell U, McFarland K (2013) Behavioral effects of clozapine, pimavanserin, and quetiapine in rodent models of Parkinson's disease and Parkinson's disease psychosis: evaluation of therapeutic ratios. Behavioural pharmacology 24, 628-632 [PubMed:23969614] [show Abstract] No safe, tolerated, and effective treatment for Parkinson's disease psychosis (PDP) is available; however, clozapine and quetiapine are often used off-label. An ideal PDP drug should have a therapeutic window that alleviates psychotic symptoms at doses that allow for maintained motor control and do not cause sedation. The present study determined the effective doses of quetiapine, clozapine, and the nondopaminergic, selective 5-HT2A inverse agonist/antagonist, pimavanserin, in an animal model of PDP and compared them with the doses that caused dopamine blockade and sedation. Augmented amphetamine-induced locomotion in rats with bilateral substantia nigra lesions was used to assess antipsychotic efficacy, whereas blockade of apomorphine-induced rotations in rats with unilateral 6-hydroxydopamine lesions was used to assess antidopaminergic action and reduction in spontaneous locomotion was used to assess sedation. The estimated therapeutic ratios for clozapine and quetiapine varied between 0.81 and 3.3. In contrast, the estimated therapeutic ratios for pimavanserin were at or above 170. These results suggest that a selective 5-HT2A inverse agonist/antagonist, such as pimavanserin, may provide distinct advantages compared with clozapine or quetiapine as a therapy for PDP. | Friedman JH (2013) Pimavanserin for the treatment of Parkinson's disease psychosis. Expert opinion on pharmacotherapy 14, 1969-1975 [PubMed:24016069] [show Abstract]
IntroductionParkinson's disease (PD) is a neurobehavioral disorder defined by its motor features. Its treatment is frequently complicated by the presence of psychotic symptoms, most prominently hallucinations and delusions. These cause major distress and are the primary cause for nursing home placement. Current treatment requires either a reduction in medications for mobility or the addition of atypical antipsychotics, none of which are approved in the United States, and which are associated with major potential drawbacks.Areas coveredInformation from extensive personal experience, a Pubmed literature search plus a direct request to Acadia Pharmaceuticals was used for this review. A brief review of the clinical problem and its current state of treatment will be followed by a discussion of pimavanserin and its potential role in treating PD psychosis (PDP). Several observations have implicated serotonin in the physiology of psychotic symptoms. Lysergic acid diethylamide, phencyclidine, and similar drugs that activate 5HT2A serotonin receptors produce psychotic syndromes, and almost all antipsychotic neuroleptics share the property of blocking the 5HT2A receptor as well as the dopamine D2 receptor. The reduced motor side effects of the second-generation antipsychotics have been ascribed to these drugs having greater 5HT2A antagonism than the first generation. Studies in animal models of psychosis have suggested benefits from drugs blocking the 5HT2A receptor alone without the motor side effects seen with D2 receptor antagonism.Expert opinionPimavanserin, a 5HT2A inverse agonist, has no motor side effects, and a remarkable safety profile that is comparable to placebo. Its antipsychotic effects coupled with its lack of motor side effects could make it an ideal drug for treating psychotic symptoms in PD, a major unmet need. One Phase III trial in PDP has demonstrated excellent tolerability and significant benefit. The FDA agreed to the filing of a planned new drug approval (NDA) for an indication in the treatment of PDP. | Kingwell K (2013) Parkinson disease: Pimavanserin could be useful for treating psychosis in Parkinson disease. Nature reviews. Neurology 9, 658 [PubMed:24247322] | Meltzer HY, Roth BL (2013) Lorcaserin and pimavanserin: emerging selectivity of serotonin receptor subtype-targeted drugs. The Journal of clinical investigation 123, 4986-4991 [PubMed:24292660] [show Abstract] Serotonin (5-hydroxytryptamine, or 5-HT) receptors mediate a plethora of physiological phenomena in the brain and the periphery. Additionally, serotonergic dysfunction has been implicated in nearly every neuropsychiatric disorder. The effects of serotonin are mediated by fourteen GPCRs. Both the therapeutic actions and side effects of commonly prescribed drugs are frequently due to nonspecific actions on various 5-HT receptor subtypes. For more than 20 years, the search for clinically efficacious drugs that selectively target 5-HT receptor subtypes has been only occasionally successful. This review provides an overview of 5-HT receptor pharmacology and discusses two recent 5-HT receptor subtype-selective drugs, lorcaserin and pimavanserin, which target the 5HT2C and 5HT2A receptors and provide new treatments for obesity and Parkinson's disease psychosis, respectively. | Price DL, Bonhaus DW, McFarland K (2012) Pimavanserin, a 5-HT2A receptor inverse agonist, reverses psychosis-like behaviors in a rodent model of Alzheimer's disease. Behavioural pharmacology 23, 426-433 [PubMed:22750845] [show Abstract] Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration in cognitive functioning. Overall, 25-50% of patients with AD also show symptoms of psychosis including hallucinations and delusions. As all available antipsychotic drugs have a 'black-box' warning for use in these patients because of increased mortality, no appropriate treatment for psychotic symptoms in AD currently exists. In the present study, we examined whether selective antagonism of 5-HT(2A) serotonin receptors has antipsychotic-like activity in an animal model of AD. Mice receiving an intracerebroventricular infusion of the amyloid β(25-35) peptide fragment showed AD-like histopathology and a psychosis-related behavioral phenotype with enhanced responses to the psychostimulants 2,5-dimethoxy-4-iodoamphetamine hydrochloride and amphetamine as well as disrupted prepulse inhibition. Treatment with pimavanserin, a selective serotonin 5-HT(2A) receptor inverse agonist, prevented 2,5-dimethoxy-4-iodoamphetamine hydrochloride-induced head twitches, reversed the augmented locomotor response to amphetamine, and normalized prepulse inhibition in mice with amyloid pathology. These data suggest that an infusion of amyloid β might induce alterations in serotonergic function that underlie a psychosis-like phenotype that can be normalized by treatment with a 5-HT(2A) inverse agonist. This in turn suggests that 5-HT(2A) inverse agonists, such as pimavanserin, might have therapeutic benefits in the treatment of psychosis in AD patients. | Meltzer HY, Elkis H, Vanover K, Weiner DM, van Kammen DP, Peters P, Hacksell U (2012) Pimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2mg/day, but does not enhance efficacy of haloperidol, 2mg/day: comparison with reference dose risperidone, 6mg/day. Schizophrenia research 141, 144-152 [PubMed:22954754] [show Abstract] Most atypical antipsychotic drugs (APDs), e.g. risperidone (RIS), produce more extensive blockade of brain serotonin (5-HT)(2A) than dopamine (DA) D(2) receptors. This distinguishes them from typical APDs, e.g. haloperidol (HAL). Our objective was to test the hypothesis that augmentation of low doses of RIS or HAL (2mg/day) with pimavanserin (PIM), a selective 5-HT(2A) inverse agonist, to enhance 5-HT(2A) receptor blockade, can achieve efficacy comparable to RIS, 6mg/day, but with lesser side effects. In a multi-center, randomized, double-blind, 6week trial, 423 patients with chronic schizophrenia experiencing a recent exacerbation of psychotic symptoms were randomized to RIS2mg+placebo (RIS2PBO), RIS2mg+PIM20mg (RIS2PIM), RIS6mg+PBO (RIS6PBO), HAL2mg+PBO (HAL2PBO), or HAL2mg+PIM20mg (HAL2PIM). Improvement in psychopathology was measured by the PANSS and CGI-S. The reduction in PANSS Total Score with RIS2PIM at endpoint was significantly greater than RIS2PBO: -23.0 vs. -16.3 (p=0.007), and not significantly different from the RIS6PBO group: -23.2 points. The percentage of patients with ≥20% improvement at day 15 in the RIS2PIM group was 62.3%, significantly greater than the RIS6PBO (42.1%; p=0.01) and the RIS2PBO groups (37.7%; p=0.002). Weight gain and hyperprolactinemia were greater in the RIS6PBO group than the RIS2PIM group but there was no difference in extrapyramidal side effects (EPS). HAL2PBO and HAL2PIM were not significantly different from each other in efficacy but HAL2PIM had less EPS at end point. Both HAL groups and RIS6PBO showed equal improvement in psychopathology at endpoint, indicating HAL 2mg/day is effective to treat an acute exacerbation in chronic schizophrenia patients. In conclusion, a sub-effective RIS dose combined with PIM to enhance 5-HT(2A) receptor blockade provided faster onset of action, and at endpoint, equal efficacy and better safety, compared to standard dose RIS. These results support the conclusion that 5-HT(2A) receptor blockade is a key component of the action of some atypical APDs and can reduce EPS due to a typical APD. | McFarland K, Price DL, Bonhaus DW (2011) Pimavanserin, a 5-HT2A inverse agonist, reverses psychosis-like behaviors in a rodent model of Parkinson's disease. Behavioural pharmacology 22, 681-692 [PubMed:21921840] [show Abstract] Parkinson's disease psychosis (PDP) is a condition for which a safe, tolerated, and effective therapy is lacking. Treatment with typical or atypical antipsychotics may be contraindicated in patients with PDP because of the potential for aggravating motor symptoms. This study used a novel animal model with features of both Parkinson's disease (PD) and psychosis to examine a potential mechanism for reversing PDP. Animals with bilateral 6-hydroxydopamine lesions of the substantia nigra displayed motoric impairments characteristic of humans with PD. In addition, they displayed augmented head twitches, augmented amphetamine-induced locomotor activity, and disrupted prepulse inhibition compared with sham controls, behavioral indices frequently used to assess antipsychotic activity in animal models. Pimavanserin, a selective 5-HT2A antagonist/inverse agonist, reversed the psychotic-like behavioral deficits, suggesting that nigrostriatal (6-hydroxydopamine) lesions induced alterations in 5-HT2A-mediated signaling. The selective 5-HT2A inverse agonist M100907, but not the selective 5-HT2C inverse agonist SB 252084 paralleled the effects of pimavanserin. Of note, the reversal of psychotic-like behaviors produced by 5-HT2A inverse agonists occurred without disrupting motor behaviors in lesioned subjects, suggesting that 5HT2A antagonism/inverse agonism may be beneficial in the treatment of PDP. | Ancoli-Israel S, Vanover KE, Weiner DM, Davis RE, van Kammen DP (2011) Pimavanserin tartrate, a 5-HT(2A) receptor inverse agonist, increases slow wave sleep as measured by polysomnography in healthy adult volunteers. Sleep medicine 12, 134-141 [PubMed:21256805] [show Abstract]
ObjectiveDetermine the effects of pimavanserin tartrate [ACP-103; N-(4-flurophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide], a selective serotonin 5-HT(2A) receptor inverse agonist, on slow wave sleep (SWS), other sleep parameters, and attention/vigilance.MethodsForty-five healthy adults were randomized to pimavanserin (1, 2.5, 5, or 20 mg) or placebo in a double-blind fashion (n=9/group). Pimavanserin or placebo was administered once daily in the morning for 13 consecutive days. The effects of pimavanserin were measured after the first dose and again after 13 days. Sleep parameters were measured by polysomnography. Effects on attention/vigilance were measured by a continuous performance task.ResultsCompared to placebo, pimavanserin significantly increased SWS following single and multiple dose administration. Pimavanserin also decreased number of awakenings. PSG variables not affected by pimavanserin included sleep period time, total sleep time, sleep onset latency, number of stage shifts, total time awake, early morning wake, and microarousal index. Changes in sleep architecture parameters, sleep profile parameters, and spectral power density parameters were consistent with a selective increase in SWS. Pimavanserin did not adversely affect performance on the continuous performance test measured in the evening before or morning after polysomnography.ConclusionsThese data suggest that pimavanserin selectively increases slow wave sleep and decreases awakenings, an effect that does not diminish with repeated administration. | Meltzer HY, Mills R, Revell S, Williams H, Johnson A, Bahr D, Friedman JH (2010) Pimavanserin, a serotonin(2A) receptor inverse agonist, for the treatment of parkinson's disease psychosis. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 35, 881-892 [PubMed:19907417] [show Abstract] Psychotic symptoms occur in up to 40% of patients with Parkinson's disease (PD). Clozapine and quetiapine, two atypical antipsychotic drugs, at doses markedly lower than those effective in schizophrenia, which, nevertheless, still cause sedation, hypotension, and other side effects, are widely used to treat psychotic symptoms in patients with PD psychosis (PDP), although quetiapine has never been shown to be effective in a placebo-controlled study. The demonstrated efficacy of clozapine in PDP has been attributed to serotonin (5-HT(2A)) receptor blockade. We postulated that pimavanserin (ACP-103), a highly selective 5-HT(2A) inverse agonist, would attenuate psychosis in patients with PDP, but avoid motoric worsening and non-motoric side effects. In this double-blind, randomized multicenter 28-day study, the tolerability and efficacy of pimavanserin was compared with placebo in 60 patients with L-DOPA or dopamine (DA) agonist-induced PDP. Motor function was evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II and III. Antipsychotic efficacy was evaluated using multiple measures from the Scale for the Assessment of Positive Symptoms (SAPS) and a UPDRS Part I psychosis-relevant item. Pimavanserin did not differentiate from placebo with regard to motor impairment, sedation, hypotension, or other side effects. The principal measures of efficacy of antipsychotic response to pimavanserin, the SAPS total domain score, only showed a trend. However, the pimavanserin-treated patients showed significantly greater improvement in some but not all measures of psychosis, including SAPS global measures of hallucinations and delusions, persecutory delusions, and the UPDRS measure of delusions and hallucinations. Pimavanserin showed significantly greater improvement in psychosis in patients with PDP at a dose which did not impair motor function, or cause sedation or hypotension Thus, pimavanserin may represent a novel treatment for PDP. Furthermore, these results support the hypothesis that attenuation of psychosis secondary to DA receptor stimulation in PDP may be achieved through selective 5-HT(2A) receptor antagonism. | Snigdha S, Horiguchi M, Huang M, Li Z, Shahid M, Neill JC, Meltzer HY (2010) Attenuation of phencyclidine-induced object recognition deficits by the combination of atypical antipsychotic drugs and pimavanserin (ACP 103), a 5-hydroxytryptamine(2A) receptor inverse agonist. The Journal of pharmacology and experimental therapeutics 332, 622-631 [PubMed:19864614] [show Abstract] Subchronic administration of the N-methyl-d-aspartate receptor antagonist, phencyclidine (PCP), in rodents has been shown to produce impairment in novel object recognition (NOR), a model of visual learning and memory. We tested the hypothesis that the selective 5-HT(2A) inverse agonists, pimavanserin and (R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl]-4-piperidinemethanol (M100907), would potentiate subeffective doses of atypical antipsychotic drugs (APDs) to reverse the NOR deficits. Female rats received vehicle or PCP (2 mg/kg b.i.d.) for 7 days, followed by a 7-day washout. Pimavanserin (3 mg/kg) or M100907 (1 mg/kg) alone, or four atypicial APDs, risperidone (0.05-0.1 mg/kg), melperone (1-3 mg/kg), olanzapine (1-2 mg/kg), or N-desmethylclozapine (1-2 mg/kg), and the typical APD, haloperidol (0.05-0.1 mg/kg), were administered alone, or in combination with pimavanserin or M100907, before NOR testing. The exploration times of objects during 3-min acquisition and retention trials, separated by a 1-min interval, were compared by analysis of variance. Vehicle-, but not PCP-treated, animals, explored the novel object significantly more than the familiar in the retention trial (p < 0.05-0.01). Pretreatment with the higher doses of the atypical APDs, but not pimavanserin, M100907, or haloperidol alone, reversed the effects of PCP. The effect of risperidone was blocked by haloperidol pretreatment. Coadministration of pimavanserin or M100907, with ineffective doses of the atypical APDs, but not haloperidol, also reversed the PCP-induced deficit in NOR. These results support the importance of 5-hydroxytryptamine(2A) receptor blockade relative to D(2) receptor blockade in the ability of atypicals to ameliorate the effect of subchronic PCP, a putative measure of cognitive dysfunction in schizophrenia. | Abbas A, Roth BL (2008) Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders. Expert opinion on pharmacotherapy 9, 3251-3259 [PubMed:19040345] [show Abstract]
BackgroundPimavanserin tartrate is the first 5-HT(2A) inverse agonist to enter clinical trials as a treatment for L-dopa-induced psychosis in Parkinson's disease and for augmentation of low-dose risperidone treatment in schizophrenia. Pimavanserin is also being evaluated as a possible anti-insomnia drug.ObjectiveTo discuss the potential of pimavanserin to fill multiple therapeutic needs.MethodsThe problems with currently approved antipsychotics and sleep agents are explored to highlight how pimavanserin might address some longstanding issues in the treatment of psychosis and insomnia.Results/conclusionsIn Phase II clinical trials, pimavanserin seemed to be safe, well-tolerated and efficacious in treating L-dopa-induced psychosis without worsening motor symptoms. Pimavanserin also potentiated the therapeutic effects of low-dose risperidone, reduced haloperidol-induced akathisia, and increased slow-wave sleep in older individuals. | Vanover KE, Weiner DM, Makhay M, Veinbergs I, Gardell LR, Lameh J, Del Tredici AL, Piu F, Schiffer HH, Ott TR, Burstein ES, Uldam AK, Thygesen MB, Schlienger N, Andersson CM, Son TY, Harvey SC, Powell SB, Geyer MA, Tolf BR, Brann MR, Davis RE (2006) 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. The Journal of pharmacology and experimental therapeutics 317, 910-918 [PubMed:16469866] [show Abstract] The in vitro and in vivo pharmacological properties of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103) are presented. A potent 5-hydroxytryptamine (5-HT)(2A) receptor inverse agonist ACP-103 competitively antagonized the binding of [(3)H]ketanserin to heterologously expressed human 5-HT(2A) receptors with a mean pK(i) of 9.3 in membranes and 9.70 in whole cells. ACP-103 displayed potent inverse agonist activity in the cell-based functional assay receptor selection and amplification technology (R-SAT), with a mean pIC(50) of 8.7. ACP-103 demonstrated lesser affinity (mean pK(i) of 8.80 in membranes and 8.00 in whole cells, as determined by radioligand binding) and potency as an inverse agonist (mean pIC(50) 7.1 in R-SAT) at human 5-HT(2C) receptors, and lacked affinity and functional activity at 5-HT(2B) receptors, dopamine D(2) receptors, and other human monoaminergic receptors. Behaviorally, ACP-103 attenuated head-twitch behavior (3 mg/kg p.o.), and prepulse inhibition deficits (1-10 mg/kg s.c.) induced by the 5-HT(2A) receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride in rats and reduced 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. ACP-103 demonstrated >42.6% oral bioavailability in rats. Thus, ACP-103 is a potent, efficacious, orally active 5-HT(2A) receptor inverse agonist with a behavioral pharmacological profile consistent with utility as an antipsychotic agent. |
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