YKP1447, a novel potential atypical antipsychotic agent

Abstract

(S)-Carbamic acid 2-[4-(4-fluoro.benzoyl)-piperidin-1-yl]-1-phenyl-ethyl ester hydrochloride (YKP1 447) is a novel "atypical" antipsychotic drug which selectively binds to serotonin (5-HT2A, KiO.61 nM, 5-HT2c, Ki=20.7 nM) and dopamine (D2, Ki=45.9 nM, D3, Ki=42.1 nM) receptors with over 10 ̃ 100-fold selectivity over the various receptors which exist in the brain. In the behavioral studies using mice, YKP1447 antagonized the apomorphine-induced cage climbing (ED50O.93 mg/kg) and DOl-induced head twitch (ED=50=0.18 mg/kg) behavior. In the dextroamphetamine-induced hyperactivity and conditioned avoidance response (CAR) paradigm in rats, YKP1447 inhibited the hyperactivity induced by amphetamine (ED50=0.54 mg/kg) and the avoidance response (ED50=0.48 mg/kg); however, unlike other antipsychotic drugs, catalepsy was observed only at much higher dose (ED5668.6 mg/kg). Based on the CAR and catalepsy results, the therapeutic index (TI) value for YKP1447 is over 100 (i.p.). These results indicate that YKP1447 has an atypical profile and less undesirable side effects than currently available drugs.