Volinanserin: Redefining antipsychotic efficacy beyond dopamine via 5-HT₂A antagonism

Newsletter # 130



In vivo studies


Current antipsychotic treatments predominantly rely on dopamine D₂ receptor antagonism, which often leads to extrapyramidal side effects and limited efficacy in addressing cognitive and negative symptoms of schizophrenia.
One promising avenue involves interference with the 5-HT₂A receptor pathway, which plays a key role in modulating cortical excitability and has been implicated in the pathophysiology of psychosis.
M100907 (Volinanserin, VOL) is a highly selective 5-HT₂A antagonist that has shown to be well tolerated in humans, exhibiting clear anti-hallucinogenic properties and limited, but potentially valuable, antipsychotic efficacy without the liabilities associated with dopamine D₂ receptor blockade.
Although M100907 did not progress to late-stage clinical development or regulatory approval, it remains a benchmark compound in preclinical research due to its exceptional selectivity and well-characterized pharmacological profile.
PCP (phencyclidine) -induced hyperlocomotion in mice serves as a robust preclinical model for the positive symptoms of schizophrenia, such as psychomotor agitation and hallucination-like behaviors. This effect arises from NMDA receptor blockade on cortical and subcortical circuits, leading to increased dopaminergic activity and cortical disinhibition—mechanisms closely aligned with the pathophysiology of psychosis.

Neurofit’s data show that Volinanserin significantly attenuated PCP-induced hyperlocomotion in mice without affecting baseline locomotor activity prior to PCP challenge, demonstrating both selectivity and translational relevance. This outcome highlights Neurofit’s expertise in applying validated behavioral models to assess novel antipsychotic mechanisms and supports the potential of 5-HT₂A antagonism as a non-dopaminergic approach in schizophrenia research.

  • Time course of locomotor activity
    of mice in the open field

    NEUROFIT website

    Left panel:
    Time-course of locomotor activity of mice in the open field.
    Locomotor activity is shown in 5-minute bins following PCP administration. Mice treated with PCP (red symbol) alone displayed a pronounced and sustained increase in locomotion, reflecting hyperactivity. Pretreatment with Volinanserin (0.03 and 0.1 mg/kg, s.c.) dose-dependently attenuated this PCP-induced hyperlocomotion (blue symbols), bringing activity levels close to those of control animals (open symbol). Volinanserin alone did not alter baseline locomotor activity prior to PCP challenge.

  • Total travelled distance of mice
    during the 1h post-PCP challenge
    NEUROFIT website

    Right panel:

    Total travelled distance of mice during the 1 h post-PCP challenge.

    Total distance travelled over the 60 minutes following PCP injection is shown. PCP produced a significant increase in locomotor activity (red column) compared with saline controls (open column). Both doses of Volinanserin (blue columns) significantly reduced the PCP-induced hyperlocomotion in a dose-dependent manner, confirming its efficacy in this schizophrenia-relevant model.



NEUROFIT offers a range of validated in vitro and in vivo screening tests for psychiatry and neurology.

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