A selective dopamine D-4 receptor antagonist, NRA0160: A preclinical neuropharmacological profile

NRA0160, 5-[2-(4-(3-fluorobenzylidene) piperidin-1-yl) ethyl]-4-(4-fluoroph enyl) thiazole-2-carboxamide, has a high affinity for human cloned dopamine D-4.2, D-4.4 and D-4.7 receptors, with Ki values of 0.5, 0.9 and 2.7 nM, r espectively. NRA0160 is over 20,000-fold more potent at the dopamine D-4.2 receptor compared with the human cloned dopamine D-2L receptor. NRA0160 has negligible affinity for the human cloned dopamine D-3 receptor (Ki=39 nM), rat serotonin (5-HT)(2A) receptors (Ki=180 nM) and rat alpha(1) adrenocept or (Ki=237 nM). NRA0160 and clozapine antagonized locomotor hyperactivity i nduced by methamphetamine (MAP) in mice. NRA0160 and clozapine antagonized MAP-induced stereotyped behavior in mice, although their effects did not ex ceed 50% inhibition, even at the highest dose given. NRA0160 and clozapine significantly induced catalepsy in rats, although their effects did not exc eed 50% induction even at the highest dose given. NRA0160 and clozapine sig nificantly reversed the disruption of prepulse inhibition (PPI) in rats pro duced by apomorphine. NRA0160 and clozapine significantly shortened the phe ncyclidine (PCP)-induced prolonged swimming latency in rats in a water maze task. These findings suggest that NRA0160 may have unique antipsychotic ac tivities without the liability of motor side effects typical of classical a ntipsychotics.