The dopamine stabilizers (S)-(-)-(3-methanesulfonyl-phenyl)-1-propyl-piperidine [(-)-OSU6162] and 4-(3-methanesulfonyl-phenyl)-1-propyl-piperidine (ACR16) show high in vivo D2 receptor occupancy, antipsychotic-like efficacy, and low potential for motor side effects in the rat

Dopamine stabilizers are a new class of compounds that have the ability to reverse both hypo- as well as hyperdopaminergia in vivo. This class, exemplified by the phenylpiperidines (S)-(-)-3-(3-methanesulfonyl- phenyl)-1-propyl-piperidine [(-)-OSU6162] and 4-(3-methanesulfonyl-phenyl)-1-propyl)-piperidine [ACR16] although lacking high in vitro binding affinity for dopamine D-2 receptor [(-)-OSU6162, K-i = 447 nM; ACR16, K-i > 1 mu M], shows functional actions, suggestive of their interaction. Hence, we evaluated in vivo D-2 occupancy of these agents in rats and correlated it to observed effects in a series of behavioral, neurochemical, and endocrine models relevant to the dopamine system and antipsychotic effect. Both (-)-OSU6162 and ACR16 showed robust dose- dependent striatal D-2 occupancy with ED50 values of 5.27 and 18.99 mg/kg s.c., respectively, and functional assays showed no partial agonism. Over an occupancy range of 37 to 87% (3-60 mg/kg) for (-)-OSU6162 and 35 to 74% (10-60 mg/kg) for ACR16, we observed both inhibitory (amphetamine-induced locomotor activity) and stimulatory effects (in habituated rats). Haloperidol, over a similar occupancy range (33-78%), potently inhibited psychostimulant activity and induced catalepsy, but it failed to activate habituated animals. In the conditioned avoidance response assay, ACR16 was clearly more efficacious than (-)OSU6162. In addition, both these compounds demonstrated significant preferential Fos induction in the nucleus accumbens compared with the dorsolateral striatum, a strong predictor of atypical antipsychotic efficacy. The results suggest that dopamine stabilizers exhibit locomotor stabilizing as well as antipsychoticlike effects, with low motor side effect liability, in a dose range that corresponds to high D-2 in vivo occupancy.