JNJ-37822681 / J&J - LARVOL DELTA

The fast-dissociating D2 antagonist antipsychotic JNJ-37822681 is a neuronal Kv7 channel opener: potential repurposing for epilepsy treatment (Neuroscience 2025) - "These effects were blocked by the Kv7 inhibitor XE-991 and were not replicated by the D2 receptor antagonist (-)-sulpiride, confirming that the observed effects of JNJ-37822681 were specifically mediated via Kv7 channel activation. In vivo, JNJ-37822681 significantly reduced the severity and frequency of pentylenetetrazole-induced seizures in C57BL mice and sound-induced seizures in genetically epilepsy-prone DBA/2 mice, with a potency comparable to retigabine. Pretreatment with XE-991 attenuated the antiseizure effects of JNJ-37822681 in both models, further supporting a Kv7-dependent mechanism of action. Given its favorable safety profile in humans and lack of the chemical liabilities associated with retigabine, JNJ-37822681 represents a compelling candidate for further development of novel ASMs."

CNS Disorders • Epilepsy • DRD2 • KCNQ1OT1

The fast-dissociating D2 antagonist antipsychotic JNJ-37822681 is a neuronal Kv7 channel opener: Potential repurposing for epilepsy treatment. (PubMed, Br J Pharmacol) - "Our study reveals that JNJ-37822681, which lacks retigabine's potential safety issues due to chemical liability and is already confirmed as safe for human use, represents a potential treatment of Kv7-related neuronal hyperexcitability disorders."

Journal • CNS Disorders • Epilepsy

EC50 images reveal reproducible spatial variation in drug affinity across single- and repeat-dose occupancy studies. (PubMed, J Cereb Blood Flow Metab) - "We investigated spatial variation in the apparent affinity of the D2 antagonist drug, JNJ-37822681, for dopamine receptors across single-dose (SD) and repeat-dose (RD) PET occupancy studies...Our findings validate EC50 images for capturing spatial variation in drug affinity and highlights the importance of accurate modeling in chronic dosing studies. LPF and SLIC-Occ provide a robust framework for analyzing occupancy data, aiding dose optimization for drug trials."

Journal

EC50 images reveal reproducible spatial variation in drug affinity in multiple PET occupancy studies (SNMMI 2024) - "Previously published studies (Te Beek, and Schmidt 2012) used conventional regional analysis of occupancy to investigate the striatal dopamine D2 receptor occupancy of JNJ-37822681, a D2 receptor antagonist, in healthy volunteers... The similarity in spatial pattern of EC50 across different studies and the asymmetry in left and right striatum indicates reproducibility of the LPF and SLIC-Occ pipeline and suggests an underlying biological cause. The higher EC50 values for RD compared to SD found here using voxel-by-voxel analysis are consistent with previous findings using regional analysis methods (Schmidt 2012, Rabiner 2023)."

DRD2

The roles of periaqueductal gray and dorsal raphe nucleus dopaminergic systems in the mechanisms of thermal hypersensitivity and depression in mice. (PubMed, J Pain) - "Microinjections of quinpirole, a dopamine D2 receptor agonist, up-regulated D2 receptor expression in dorsal raphe nucleus and reduced depressive behaviors and thermal hypersensitivity with chronic unpredictable mild stress, while dorsal raphe nucleus injections of JNJ-37822681, an antagonist of D2 receptors, had the reciprocal effect on dopamine D2 receptor expression and behaviors...Collectively these results demonstrated the specific role of ventrolateral periaqueductal gray and dorsal raphe nucleus dopaminergic systems in the regulation of pain and depression comorbidity in mice. PERSPECTIVE: The current study provides insights into the complex mechanisms underlying thermal hypersensitivity induced by depression, and the findings suggest that pharmacological and chemogenetic modulation of dopaminergic systems in the ventrolateral periaqueductal gray and dorsal raphe nucleus may be a promising therapeutic strategy to simultaneously mitigate pain and depression."

Journal • Preclinical • CNS Disorders • Depression • Immunology • Mood Disorders • Pain • Psychiatry • DRD2

D(2)-receptor occupancy measurement of JNJ-37822681, a novel fast off-rate D(2)-receptor antagonist, in healthy subjects using positron emission tomography: single dose versus steady state and dose selection (Psychopharmacology (Berl)) - P=NA, N=12; Steady state was reached after 4-5 days of twice daily dosing; JNJ-37822681 plasma concentrations of 3.17 to 63.0ng/mL resulted in D(2) occupancies of 0% to 62%; The concentration leading to 50% occupancy was 18.5ng/mL (coefficient of variation 3.9%) after single dose and 26.0ng/mL (8.2%) at steady state

Clinical data • Schizophrenia

A double-blind, randomized, placebo-controlled study with JNJ-37822681, a novel, highly selective, fast dissociating D(2) receptor antagonist in the treatment of acute exacerbation of schizophrenia (Eur Neuropsychopharmacol) - P2, N=498; All JNJ-37822681 dose groups and the olanzapine group showed greater reduction in PANSS total score from baseline to week 6 versus PBO (all p-values<0.001); All JNJ-37822681 groups showed improvement versus PBO from baseline to week 6 in the PANSS subscales, Marder factors, Clinical global impression of severity, and in the subjective well-being on neuroleptics scale (all p-values<0.05)

P2 data • Schizophrenia

Does early improvement predict response to the fast-dissociating D(2) receptor antagonist JNJ-37822681 in patients with acute schizophrenia? (Eur Neuropsychopharmacol) - P2, N=499; NCT00728195; Early improvement (day 3) in PANSS score had the highest predictive value as a single factor across all JNJ-37822681 doses; At a specificity of 70%, sensitivity for predicting week-6 response was: 0.60, 0.64, and 0.74 in the 10mg, 20mg, and 30mg bid JNJ-37822681 groups, respectively

P2 data • Schizophrenia

Investigational Dopamine Antagonists for the Treatment of Schizophrenia (SIRS 2020) - "Brexpiprazole and cariprazine, which were agents listed as ‘investigational dopamine antagonists,’ have just received FDA approval...However, three other agents, including BL-1020, ITI-007, and JNJ-37822681, have solid published data showing their efficacy and the potential to provide enhanced safety than the currently available atypical antipsychotics. Other agents such as L-THP, Lu AF35700, S33138, and SB- 773812 are currently under vigorous investigation...Thus, it may become the first new pharmacotherapy, after clozapine, for patients with treatment-resistant schizophrenia if the phase III trial shows positive results...However, much as ‘all roads lead to Rome’ all the studied agents to date lead to alteration of dopamine receptors, either in the form of agonist/partial agonist or antagonist activity. Thus, the development of agents with dopamine antagonist properties will and should continue, unless a novel agent with an extradopaminergic mechanism, with its..."