Received for publication February 14, 2006.
Revised April 25, 2006.
Accepted for publication April 26, 2006.

The dopamine stabilizers (-)-OSU6162 and ACR16 show high in vivo D₂ receptor occupancy, antipsychotic- like efficacy and low potential for motor side effects in the rat

Abstract

"Dopamine stabilizers" is a new class of compounds which have the ability to reverse both hypo as well as hyperdopaminergia in vivo. This class, exemplified by the phenylpiperidines (-)-OSU6162 & ACR16, although lacking high in vitro binding affinity for dopamine D₂ receptor ((-)-OSU6162:Ki 447nM, ACR16:Ki >1µM) show functional actions suggestive of their interaction. Hence we evaluated in vivo D₂ 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 D₂ 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 37-87% (3-60 mg/kg) for (-)-OSU6162 and 35-74% (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 failed to activate habituated animals. In the conditioned avoidance response (CAR) assay, ACR16 was clearly more efficacious than (-)-OSU6162. Also both these compounds demonstrated significant preferential Fos induction in the nucleus accumbens as compared to the dorsolateral striatum, a strong predictor of atypical antipsychotic efficacy. The results suggest that dopamine stabilizers exhibit locomotor stabilizing as well as antipsychotic-like effects with low motor side-effect liability, in a dose range that corresponds to high D₂ in vivo occupancy.

Key words: CAR, D2 receptor occupancy, Dopamine stabilizers, Fos, antipsychotic, catalepsy