Abstract
Introduction: Brilaroxazine (RP5063) displays high affinity for serotonin (5-HT) 1A/2A/2B/7 and dopamine (D) 2/3/4 and moderate affinity for D1, serotonin transporter (SERT), and nicotinic acetylcholine receptor, α4β2. These receptors are associated with multiple psychological disorders.
Methods: The pre-clinical assessment involved three standard models emulating human schizophrenia symptoms. The apomorphine climbing test (Protais et al., 1976), in 5 groups of 10 NMRI mice, compared brilaroxazine (1, 3, and 10 mg/kg i.p.), haloperidol (0.5 mg/kg i.p.), and vehicle. The apomorphine-induced deficit in prepulse inhibition (PPI) (Geyer et al., 2001), in 5 groups of 15 Wistar rats, compared brilaroxazine (3, 10, and 30 mg/kg i.p.), haloperidol (1 mg/kg), and vehicle. The dizocilpine effect on locomotion, stereotypy, and rearing (Rung et al. 2005), in 6 groups of 10 Wistar rats, compared brilaroxazine (3, 10, and 30 mg/kg i.p.), olanzapine (6 mg/kg i.p.) and vehicle with (and without) induction.
Results: Brilaroxazine decreased apomorphine-induced climbing across the 1, 3, and 10 mg/kg doses versus controls (p<0.001). This compound dose-dependently reversed the apomorphine-induced PPI effects- 10 mg/kg at 87 dB (p<0.05) and 30 mg/kg at all levels (p<0.01). In the dizocilpine-induced model, it decreased versus vehicle controls: (1) spontaneous locomotor activity by 15% (p<0.05, 3 mg/kg), 40% (p<0.001, 10 mg/kg) and 30% (p<0.01, 30 mg/kg); (2) induced locomotion by 25% (p<0.05, 3 mg/kg), 49% (p<0.01, 10 mg/kg), and 47% (p<0.01, 30 mg/kg), (3) stereotypy by 51% and 58% (p<0.001, 10- and 30-mg/kg, respectively), and rearing (only 10 mg/kg, NS).
Conclusion: Brilaroxazine showed animal proof-of-concept activity by mitigating pharmacologically induced behaviors in rodents reflecting psychotic symptoms in humans.