A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model

Vanover, Kimberly E.; Betz, Adrienne J.; Weber, Suzanne M.; Bibbiani, Francesco; Kielaitė, Aistė; Weiner, David M.; Davis, Robert E.; Chase, Thomas N.; Salamone, John D.

doi:10.1016/j.pbb.2008.04.010

Cited by 67 publications

(35 citation statements)

References 56 publications

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“…These results are supported by adverse event data and are consistent with a recent report that pimavanserin reduced tremor in an animal model of parkinsonian tremor and reduced levodopa-induced dyskinesias in monkeys rendered parkinsonian with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) (Vanover et al, 2008).…”

Section: Effects On Motor Function and Tolerabilitysupporting

confidence: 91%

Pimavanserin, a Serotonin2A Receptor Inverse Agonist, for the Treatment of Parkinson's Disease Psychosis

Meltzer

Mills

Revell

et al. 2009

Neuropsychopharmacol

269

173

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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 psychosisrelevant 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.

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Section: Effects On Motor Function and Tolerabilitysupporting

confidence: 91%

Pimavanserin, a Serotonin2A Receptor Inverse Agonist, for the Treatment of Parkinson's Disease Psychosis

Meltzer

Mills

Revell

et al. 2009

Neuropsychopharmacol

269

173

View full text Add to dashboard Cite

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“…In agreement with an importance of selectively antagonizing 5-HT 2A receptors over off-target receptors, pimavanserin (ACP-103) effectively alleviated L-DOPA-induced dyskinesia in the MPTP-lesioned, parkinsonian monkey (Vanover et al, 2008) and patients with idiopathic PD (Roberts, 2006;Mills et al, 2008), without impairing L-DOPA antiparkinsonian action. In contrast to the atypical antipsychotics, pimavanserin is a relatively selective 5-HT 2A inverse agonist, although it also exhibits affinity at 5-HT 2C receptors (Vanover et al, 2006).…”

Section: -Ht 1a Agonist R-(ϩ)-8-oh-dpatmentioning

confidence: 83%

Anatomically Selective Serotonergic Type 1A and Serotonergic Type 2A Therapies for Parkinson’s Disease: An Approach to Reducing Dyskinesia without Exacerbating Parkinsonism?

Huot¹,

Fox²,

Newman‐Tancredi³

et al. 2011

The Journal of Pharmacology and Experimental Therapeutics

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L-DOPA remains the most effective treatment for Parkinson's disease (PD). However, long-term administration of L-DOPA is compromised by complications, particularly dyskinesia. Serotonergic type 1A (5-HT 1A ) receptor agonists and serotonergic type 2A (5-HT 2A ) receptor antagonists were, until recently, considered to be promising therapies against dyskinesia. However, there have been some recent high-profile failures in clinical trials, notably with sarizotan, and it seems that these classes of drugs may also impair L-DOPA antiparkinsonian efficacy. A simple explanation for the loss of antiparkinsonian benefit might be lack of good selectivity of these compounds for their respective targets, particularly with respect to off-target actions on dopaminergic receptors or poor dose selection in clinical studies. However, such explanations do not hold broadly when considering the actions of all compounds studied to date, whether in animal models or clinical trials. Here, we review 5-HT 1A and 5-HT 2A receptor function in PD and provide an anatomically based rationale as to why in some instances 5-HT 1A -and 5-HT 2A -modulating drugs might worsen parkinsonism, in addition to reducing dyskinesia. We propose that, in addition to selectivity for specific receptor subtypes, to target 5-HT 1A and 5-HT 2A receptors to alleviate dyskinesia, without worsening parkinsonism, it will be necessary to develop compounds that display anatomical selectivity, targeting corticostriatal transmission, while avoiding 5-HT receptors on ascending serotonergic and dopaminergic inputs from the raphe and substantia nigra, respectively.

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“…It should be noted though that both clozapine and quetiapine bind to several other serotonergic and nonserotonergic receptors (Huot et al, 2011a) and that, although their antidyskinetic efficacy is usually attributed to antagonizing 5-HT 2A receptors, a contribution of these other targets cannot be excluded, therefore limiting the interpretation of these pharmacological studies. More selective compounds such as the Renantiomer of 3,4-methylenedioxymethamphetamine (MDMA) (Huot et al, 2011c) and pimavanserin (ACP-103) (Vanover et al, 2008) also alleviated LID in the MPTP-lesioned NHP. In clinical settings, clozapine (Durif et al, 2004) as well as the more selective 5-HT 2A antagonists ritanserin (Maertens de Noordhout and Delwaide, 1986;Meco et al, 1988) and pimavanserin (Roberts, 2006) all alleviated dyskinesia.…”

Section: B 5-ht 2a Receptorsmentioning

confidence: 99%

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

Huot

Johnston²,

Koprich³

et al. 2013

Pharmacological Reviews

294

230

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A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model

Cited by 67 publications

References 56 publications

Pimavanserin, a Serotonin2A Receptor Inverse Agonist, for the Treatment of Parkinson's Disease Psychosis

Pimavanserin, a Serotonin2A Receptor Inverse Agonist, for the Treatment of Parkinson's Disease Psychosis

Anatomically Selective Serotonergic Type 1A and Serotonergic Type 2A Therapies for Parkinson’s Disease: An Approach to Reducing Dyskinesia without Exacerbating Parkinsonism?

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

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