F-15,063 is an orally active potentialantipsychotic, and anantagonist at theD2/D3 receptors,partial agonist at theD4 receptor, and agonist at the5-HT1A receptors. It has greater efficacy at the 5-HT1A receptors than other antipsychotics, such asclozapine,aripiprazole, andziprasidone. This greater efficacy may lead to enhanced antipsychotic properties, as antipsychotics that lack 5-HT1A affinity are associated with increased risk ofextrapyramidal symptoms, and lack of activity against the negative symptoms ofschizophrenia.[1]
As expression ofimmediate-early gene (IEG) in certain brain regions may represent markers of anti-psychotic activity, expression of immediate-early genemRNA in theprefrontal cortex andstriatum was measured. Treatment with F-15,063 resulted in induction ofc-fos andfosB 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 blockedamphetamine andketamine inducedhyperlocomotion, but did not affect baseline, spontaneouslocomotor activity. In addition, F-15,063 did not producecatalepsy, a side effect of other antipsychotics, such ashaloperidol. This inhibition of catalepsy is 5-HT1A receptor mediated, as pretreatment with the 5-HT1A antagonistWAY-100635 reinstated catalepsy. The level of catalepsy did not increase with chronic dosing, and there was no evidence forserotonin 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.
^Assié, MB (June 2007). "F15063, a potential antipsychotic with dopamine D(2)/D(3) antagonist, 5-HT(1A) agonist and D(4) partial agonist properties: (IV) duration of brain D2-like receptor occupancy and antipsychotic-like activity versus plasma concentration in mice".Naunyn-Schmiedeberg's Archives of Pharmacology.375 (4):241–50.doi:10.1007/s00210-007-0162-x.PMID17453175.S2CID20594732.
