F-15,063 is an orally active potential
antipsychotic, and an
antagonist at the
D2/
D3 receptors,
partial agonist at the
D4 receptor, and agonist at the
5-HT1A receptors. It has greater efficacy at the 5-HT1A receptors than other antipsychotics, such as
clozapine,
aripiprazole, and
ziprasidone. This greater efficacy may lead to enhanced antipsychotic properties, as antipsychotics that lack 5-HT1A affinity are associated with increased risk of
extrapyramidal symptoms, and lack of activity against the negative symptoms of
schizophrenia.[1]
As expression of
immediate-early gene (IEG) in certain brain regions may represent markers of anti-psychotic activity, expression of immediate-early gene
mRNA in the
prefrontal cortex and
striatum was measured. Treatment with F-15,063 resulted in induction of c-fos and fosB mRNA expression in the prefrontal cortex. In the striatum, F-15,063 treatment resulted in induction of all
IEGs studied (c-fos, fosB,
zif268,
c-jun,
junB,
nor1,
nur77,
arc).[2]
F-15,063 was tested in several animal models that predict antipsychotic activity to help determine the behavioral profile. Administration of F-15,063 blocked
amphetamine and
ketamine induced hyperlocomotion, but did not affect baseline, spontaneous locomotor activity. In addition, F-15,063 did not produce
catalepsy, a side effect of other antipsychotics, such as
haloperidol. This inhibition of catalepsy is 5-HT1A receptor mediated, as pretreatment with the 5-HT1A antagonist
WAY-100635 reinstated catalepsy. The level of catalepsy did not increase with chronic dosing, and there was no evidence for
serotonin syndrome at clinically relevant doses.[3]
Plasma levels of F-15,063 decreased seven-fold 4 hours after oral administration, and 25-fold after 8 hours. Despite this, there was still a high (65%) level of central D2 occupancy at 4 hours, and it retained its full antipsychotic potential at this time point. Even after 8 hours, F-15,063 still demonstrated some central D2 occupancy, and retained some antipsychotic activity.[4]
^Bruins Slot, LA (October 2009). "F15063, a potential antipsychotic with dopamine D(2)/D(3) receptor antagonist and 5-HT(1A) receptor agonist properties: influence on immediate-early gene expression in rat prefrontal cortex and striatum". European Journal of Pharmacology. 620 (1–3): 27–35.
doi:
10.1016/j.ejphar.2009.08.019.
PMID19695244.
F-15,063 is an orally active potential
antipsychotic, and an
antagonist at the
D2/
D3 receptors,
partial agonist at the
D4 receptor, and agonist at the
5-HT1A receptors. It has greater efficacy at the 5-HT1A receptors than other antipsychotics, such as
clozapine,
aripiprazole, and
ziprasidone. This greater efficacy may lead to enhanced antipsychotic properties, as antipsychotics that lack 5-HT1A affinity are associated with increased risk of
extrapyramidal symptoms, and lack of activity against the negative symptoms of
schizophrenia.[1]
As expression of
immediate-early gene (IEG) in certain brain regions may represent markers of anti-psychotic activity, expression of immediate-early gene
mRNA in the
prefrontal cortex and
striatum was measured. Treatment with F-15,063 resulted in induction of c-fos and fosB mRNA expression in the prefrontal cortex. In the striatum, F-15,063 treatment resulted in induction of all
IEGs studied (c-fos, fosB,
zif268,
c-jun,
junB,
nor1,
nur77,
arc).[2]
F-15,063 was tested in several animal models that predict antipsychotic activity to help determine the behavioral profile. Administration of F-15,063 blocked
amphetamine and
ketamine induced hyperlocomotion, but did not affect baseline, spontaneous locomotor activity. In addition, F-15,063 did not produce
catalepsy, a side effect of other antipsychotics, such as
haloperidol. This inhibition of catalepsy is 5-HT1A receptor mediated, as pretreatment with the 5-HT1A antagonist
WAY-100635 reinstated catalepsy. The level of catalepsy did not increase with chronic dosing, and there was no evidence for
serotonin syndrome at clinically relevant doses.[3]
Plasma levels of F-15,063 decreased seven-fold 4 hours after oral administration, and 25-fold after 8 hours. Despite this, there was still a high (65%) level of central D2 occupancy at 4 hours, and it retained its full antipsychotic potential at this time point. Even after 8 hours, F-15,063 still demonstrated some central D2 occupancy, and retained some antipsychotic activity.[4]
^Bruins Slot, LA (October 2009). "F15063, a potential antipsychotic with dopamine D(2)/D(3) receptor antagonist and 5-HT(1A) receptor agonist properties: influence on immediate-early gene expression in rat prefrontal cortex and striatum". European Journal of Pharmacology. 620 (1–3): 27–35.
doi:
10.1016/j.ejphar.2009.08.019.
PMID19695244.