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.
"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, Ki = 447 nM; ACR16, Ki > 1 microM], 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.
Natesan
Sridhar
S
Schizophrenia Program and PET Centre, Toronto, Ontario, Canada.
Svensson
Kjell A
KA
Reckless
Greg E
GE
Nobrega
José N
JN
Barlow
Karen B L
KB
Johansson
Anette M
AM
Kapur
Shitij
S
D000818:Animals; D014150:Antipsychotic Agents; D001362:Avoidance Learning / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D015259:Dopamine Agents / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D018492:Dopamine Antagonists / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000523:psychology*; D006220:Haloperidol / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D011388:Prolactin / Q000097:blood; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012110:Reserpine / Q000378:metabolism
D014150:Antipsychotic Agents; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; D017448:Receptors, Dopamine D2; C109513:OSU 6162; D004295:Dihydroxyphenylalanine; D012110:Reserpine; D011388:Prolactin; C483720:pridopidine; D006220:Haloperidol