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Nonclinical characterization of ACP-204, a novel selective serotonin receptor subtype 2A receptor inverse agonist

Burstein, Ethan S ; Olsson, Roger LU orcid ; Skold, Niklas ; Jansen, Karl Erik ; Azar, Marc ; Sandiego, Christine ; Ridler, Khanum ; Rabiner, Eugenii A ; Rhodes, Gerry and Dey, P Markus , et al. (2026) In Journal of Pharmacology and Experimental Therapeutics 393(6).
Abstract

Pimavanserin was the first US Food and Drug Administration approved antipsychotic drug that does not block D2 dopamine receptors at therapeutic doses. Pimavanserin is a selective 5-HT2A receptor inverse agonist that reduces the frequency of hallucinations and delusions associated with Parkinson disease. Despite these attributes, pimavanserin prolongs the QT interval at therapeutic doses, limiting the dose to 34 mg. In addition, pimavanserin has a 57-hour half-life, and reaches steady state in approximately 12 days. ACP-204 was identified as a compound with subnanomolar affinity in radioligand binding assays, and subnanomolar inverse agonist and antagonist potency at 5-HT2A receptors in cell-based functional assays. ACP-204 had 13-fold... (More)

Pimavanserin was the first US Food and Drug Administration approved antipsychotic drug that does not block D2 dopamine receptors at therapeutic doses. Pimavanserin is a selective 5-HT2A receptor inverse agonist that reduces the frequency of hallucinations and delusions associated with Parkinson disease. Despite these attributes, pimavanserin prolongs the QT interval at therapeutic doses, limiting the dose to 34 mg. In addition, pimavanserin has a 57-hour half-life, and reaches steady state in approximately 12 days. ACP-204 was identified as a compound with subnanomolar affinity in radioligand binding assays, and subnanomolar inverse agonist and antagonist potency at 5-HT2A receptors in cell-based functional assays. ACP-204 had 13-fold less affinity for 5-HT2C receptors in radioligand binding, and 30- to 100-fold less potency at 5-HT2C in the functional assays, and was over 1000-fold selective against over 70 other targets. ACP-204 had 9-fold lower potency inhibiting human ether-à-go-go-related gene than pimavanserin, and lower potency at Cav1.2 L-type calcium and Nav1.5 sodium channels, all channels associated with cardiovascular function. ACP-204 was active in 3 rodent models of schizophrenia, was orally active, and potently engaged with central 5-HT2A receptors in nonhuman primates. Long-term toxicity studies demonstrated wide safety margins, and pharmacokinetic modeling predicted a 14.7 to 21.7 hours half-life in humans. It is anticipated that reducing the potential for QT prolongation will allow greater dosing flexibility with ACP-204 compared with pimavanserin; additionally, a shorter half-life may provide faster onset of action because of plasma concentrations reaching steady state sooner. ACP-204 is currently being evaluated for efficacy and safety in Alzheimer disease psychosis and Lewy body dementia psychosis. SIGNIFICANCE STATEMENT: Psychotic disorders remain a major source of burden and disability worldwide, with current treatments limited by inadequate efficacy or significant side effects. ACP-204 is a novel 5-HT2A receptor inverse agonist/antagonist being evaluated clinically for its potential to treat Alzheimer disease psychosis and Lewy body dementia psychosis. Comprehensive nonclinical evaluations shown herein demonstrate that ACP-204 has optimized pharmacodynamic properties resulting in a favorable safety/tolerability profile, a broad therapeutic index, and promising effectiveness.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Pharmacology and Experimental Therapeutics
volume
393
issue
6
article number
104932
publisher
American Society for Pharmacology and Experimental Therapeutics
external identifiers
  • pmid:42208178
  • scopus:105040607665
ISSN
1521-0103
DOI
10.1016/j.jpet.2026.104932
language
English
LU publication?
yes
additional info
Copyright © 2026 The Author(s). Published by Elsevier Inc. All rights reserved.
id
edb4a14a-b4fa-4aef-ae8a-979b6edd5571
date added to LUP
2026-06-10 23:35:54
date last changed
2026-08-07 13:50:20
@article{edb4a14a-b4fa-4aef-ae8a-979b6edd5571,
  abstract     = {{<p>Pimavanserin was the first US Food and Drug Administration approved antipsychotic drug that does not block D2 dopamine receptors at therapeutic doses. Pimavanserin is a selective 5-HT2A receptor inverse agonist that reduces the frequency of hallucinations and delusions associated with Parkinson disease. Despite these attributes, pimavanserin prolongs the QT interval at therapeutic doses, limiting the dose to 34 mg. In addition, pimavanserin has a 57-hour half-life, and reaches steady state in approximately 12 days. ACP-204 was identified as a compound with subnanomolar affinity in radioligand binding assays, and subnanomolar inverse agonist and antagonist potency at 5-HT2A receptors in cell-based functional assays. ACP-204 had 13-fold less affinity for 5-HT2C receptors in radioligand binding, and 30- to 100-fold less potency at 5-HT2C in the functional assays, and was over 1000-fold selective against over 70 other targets. ACP-204 had 9-fold lower potency inhibiting human ether-à-go-go-related gene than pimavanserin, and lower potency at Cav1.2 L-type calcium and Nav1.5 sodium channels, all channels associated with cardiovascular function. ACP-204 was active in 3 rodent models of schizophrenia, was orally active, and potently engaged with central 5-HT2A receptors in nonhuman primates. Long-term toxicity studies demonstrated wide safety margins, and pharmacokinetic modeling predicted a 14.7 to 21.7 hours half-life in humans. It is anticipated that reducing the potential for QT prolongation will allow greater dosing flexibility with ACP-204 compared with pimavanserin; additionally, a shorter half-life may provide faster onset of action because of plasma concentrations reaching steady state sooner. ACP-204 is currently being evaluated for efficacy and safety in Alzheimer disease psychosis and Lewy body dementia psychosis. SIGNIFICANCE STATEMENT: Psychotic disorders remain a major source of burden and disability worldwide, with current treatments limited by inadequate efficacy or significant side effects. ACP-204 is a novel 5-HT2A receptor inverse agonist/antagonist being evaluated clinically for its potential to treat Alzheimer disease psychosis and Lewy body dementia psychosis. Comprehensive nonclinical evaluations shown herein demonstrate that ACP-204 has optimized pharmacodynamic properties resulting in a favorable safety/tolerability profile, a broad therapeutic index, and promising effectiveness.</p>}},
  author       = {{Burstein, Ethan S and Olsson, Roger and Skold, Niklas and Jansen, Karl Erik and Azar, Marc and Sandiego, Christine and Ridler, Khanum and Rabiner, Eugenii A and Rhodes, Gerry and Dey, P Markus and Pathak, Sanjeev}},
  issn         = {{1521-0103}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{6}},
  publisher    = {{American Society for Pharmacology and Experimental Therapeutics}},
  series       = {{Journal of Pharmacology and Experimental Therapeutics}},
  title        = {{Nonclinical characterization of ACP-204, a novel selective serotonin receptor subtype 2A receptor inverse agonist}},
  url          = {{http://dx.doi.org/10.1016/j.jpet.2026.104932}},
  doi          = {{10.1016/j.jpet.2026.104932}},
  volume       = {{393}},
  year         = {{2026}},
}