RESUMO
SYA16263 exhibited moderate radioligand binding affinity at the D2 receptor and produced inhibition of apomorphine-induced climbing behavior in mice with an ED50 value of 3.88â¯mg/kg IP, predicting potential antipsychotic effects in humans. Analysis of plasma and brains from rats injected IP with SYA16263 over the course of 24â¯h revealed a log [brain]/[plasma] (log BB) at Cmax observed equal to 1.08, indicating that SYA16263 enters the brain and is predicted to cross the blood brain barrier (BBB) readily. When tested in animal behavior tests for catalepsy, SYA16263 did not produce catalepsy at doses up to 19 times the apomorphine ED50 value predicting little or no extra-pyramidal (EPS) side effects in humans. This is similar to aripiprazole, which is associated with a low incidence of EPS in humans, but unlike haloperidol which is known to cause severe EPS in humans. Functional activities for SYA16263 show that it acts as a D2 agonist at both the Gi and ß-arrestin pathways, similar to, but better than aripiprazole, which could account for the absence of the catalepsy observed. Taken together, the receptor binding profile, the functional status, the animal behavioral tests and the log BB value, all provide evidence for further pre-clinical testing of SYA16263 as a potential antipsychotic agent with an interesting profile and a unique mechanism of action resulting in no EPS even up to 19 times the ED50 value.
