QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.102905v1 318/2/810    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Natesan, S. Articles by Kapur, S. Search for Related Content PubMed PubMed Citation Articles by Natesan, S. Articles by Kapur, S.

NEUROPHARMACOLOGY

The Dopamine Stabilizers (S)-(-)-(3-Methanesulfonyl-phenyl)-1-propyl-piperidine [(-)-OSU6162] and 4-(3-Methanesulfonylphenyl)-1-propyl-piperidine (ACR16) Show High in Vivo D₂ Receptor Occupancy, Antipsychotic-Like Efficacy, and Low Potential for Motor Side Effects in the Rat

Schizophrenia Program and PET Centre (S.N., G.E.R., S.K.) and Neuroimaging Research Section (J.N.N., K.B.L.B.), Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Lilly Research Laboratories, Indianapolis, Indiana (K.A.S., A.M.J.); and Departments of Pharmacology (J.N.N.) and Psychiatry (S.K.), University of Toronto, Toronto, Ontario, Canada

"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 D₂ receptor [(-)-OSU6162, K_i = 447 nM; ACR16, K_i > 1 µM], shows 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 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 antipsychotic-like effects, with low motor side effect liability, in a dose range that corresponds to high D₂ in vivo occupancy.

Address correspondence to: Dr. Shitij Kapur, Centre for Addiction and Mental Health, ARF Site, 33 Russell St., Toronto, ON, Canada M5S 2S1. E-mail: shitij_kapur{at}camh.net