In vitro and in vivo pharmacological profile of 4-(4-fluorobenzylidene)-1-{2-[5-(4-fluorophenyl)-1 H -pyrazol-4-yl] ethyl} piperidine (NRA0161)

Atypical antipsychotic properties of 4-(4-fluorobenzylidene)-1-{2-[5-(4-fluorophenyl)-1 H -pyrazol-4-yl]ethyl} piperidine (NRA0161) were investigated by in vitro receptor affinities, in vivo receptor occupancies and findings were compared with those of risperidone and haloperidol in rodent behavioral studies. In in vitro receptor binding studies, NRA0161 has a high affinity for human cloned dopamine D 4 and 5-HT 2A receptor with Ki values of 1.00 and 2.52 nM, respectively. NRA0161 had a relatively high affinity for the α 1 adrenoceptor (Ki; 10.44 nM) and a low affinity for the dopamine D 2 receptor (Ki; 95.80 nM). In in vivo receptor binding studies, NRA0161 highly occupied the 5-HT 2A receptor in rat frontal cortex. In contrast, NRA0161 did not occupy the striatal D 2 receptor. In behavioral studies, NRA0161, risperidone and haloperidol antagonized the locomotor hyperactivity in mice, as induced by methamphetamine (MAP). At a higher dosage, NRA0161, risperidone and haloperidol dose-dependently antagonized the MAP–induced stereotyped behavior in mice and NRA0161 dose-dependently and significantly induced catalepsy in rats. The ED 50 value in inhibiting the MAP–induced locomotor hyperactivity was 30 times lower than that inhibiting the MAP–induced stereotyped behavior and 50 times lower than that which induced catalepsy.