Pharmacological profile of the new potent neuroleptic ocaperidone (R 79,598).
Ocaperidone, a new benzisoxazolyl piperidine neuroleptic, was compared with haloperidol, risperidone and ritanserin in a large series of pharmacological tests. Ocaperidone inhibited dopamine agonist (apomorphine, amphetamine or cocaine)-induced behavioral effects at low doses (0.014-0.042 mg/kg) and was, thereby, equipotent with haloperidol (0.016-0.024 mg/kg) and 2.0 to 8.3 times more potent than risperidone. Ocaperidone completely blocked the dopamine agonist behavior at slightly higher doses (0.064 mg/kg) and was, thereby, more potent and efficacious than haloperidol (0.097-0.13 mg/kg) and risperidone (0.59-1.17 mg/kg). The dissociation between inhibition of apomorphine behavior and induction of catalepsy was as high for ocaperidone (22) as for risperidone (20) and higher than for haloperidol (8), suggesting risperidone-like low extrapyramidal side effect liability. Ocaperidone also antagonized serotonin agonist (tryptamine, mescaline or 5-hydroxytryptophan)-induced behavioral effects (0.011-0.064 mg/kg) and was, thereby, equipotent with risperidone (0.014-0.056 mg/kg) and at least as potent as ritanserin (0.037-0.13 mg/kg). Ocaperidone displayed its serotonin and dopamine antagonism at the same dose levels, in contrast to risperidone, which was a predominant serotonin antagonist. Apart from protection from compound 48/80 lethality (0.042 mg/kg) and norepinephrine lethality (0.097 mg/kg), which were not considered to hinder its clinical application, no additional secondary effects were observed at low doses of ocaperidone. In the apomorphine test in dogs, ocaperidone was very potent (i.v., s.c. and p.o. ED50 values: less than 1.0 micrograms/kg) and showed a rapid onset (less than 0.5 h) and long duration of action (24 h) after p.o. administration. Ocaperidone is concluded to be a highly potent and efficacious dopamine-D2 antagonist with concomitant, equivalent serotonin 5-HT2 antagonism. Ocaperidone is expected to exert pronounced haloperidol-like effects on the positive symptoms of schizophrenic patients but with risperidone-like low extrapyramidal side effect liability and improved patient compliance.
Janssen Research Foundation, Beerse, Belgium.
A A
AA
Megens
F H
FH
Awouters
T F
TF
Meert
K H
KH
Schellekens
C J
CJ
Niemegeers
P A
PA
Janssen
D000818:Animals; D000932:Antiemetics / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000633:toxicity; D001058:Apomorphine / Q000037:antagonists & inhibitors; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D004285:Dogs; D015259:Dopamine Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018492:Dopamine Antagonists; D004435:Eating / Q000187:drug effects; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D007928:Lethal Dose 50; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009132:Muscles / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology* / Q000633:toxicity; D011187:Posture / Q000502:physiology; D011744:Pyrimidinones / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D018967:Risperidone; D016713:Ritanserin / Q000494:pharmacology; D012701:Serotonin / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects
D000932:Antiemetics; D014150:Antipsychotic Agents; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D007555:Isoxazoles; D018377:Neurotransmitter Agents; D010880:Piperidines; D011744:Pyrimidinones; D012702:Serotonin Antagonists; D016713:Ritanserin; C072259:ocaperidone; D012701:Serotonin; D006220:Haloperidol; D018967:Risperidone; D001058:Apomorphine