CI-943, a potential antipsychotic agent. II. Neurochemical effects.
The effects of CI-943 (a novel 8-ethyl-7,8-dihydro-1,3,5-trimethyl-1H-imidazo[1,2-c]pyrazolo[3,4- e]pyrimidine compound exhibiting a favorable antipsychotic profile in animal tests) on neurochemical parameters related to biogenic amine neurons have been studied in rat brain. CI-943 (1-40 mg/kg p.o. and 20 mg/kg i.p.) accelerated the turnover of dopamine (DA) in rat brain as demonstrated by the enhancement of levels of the DA metabolites homovanillic acid, 3,4-dihydroxyphenylacetic acid or 3-methoxytyramine and by the enhancement rate of DA synthesis in either striatum or mesolimbic regions. These increases in DA turnover induced by CI-943 are not due to DA receptor blockade as CI-943, unlike known antipsychotics, did not exhibit affinity for DA receptors either in vitro or in vivo and did not affect rat serum basal prolactin levels. Amfonelic acid enhanced the action of haloperidol in increasing striatal homovanillic acid with no effect on that of CI-943 and clozapine, suggesting that CI-943, like clozapine, would be predicted to have a low risk of extrapyramidal side effects as compared to haloperidol. Chronic administration of CI-943 (40 mg/kg i.p.) to rats for 28 days did not affect the affinity or number of striatal DA receptors; in comparison haloperidol (0.5 mg/kg i.p.) caused an increase in number of DA receptors with no change in affinity. Measures of serotonergic function were increased; noradrenergic function was not affected by CI-943, nor did it exhibit affinity for a number of central nervous system receptors in vitro. The molecular mechanism by which CI-943 increases brain DA turnover is not known at this time but appears to be unique in comparison to known antipsychotic agents.
Pugsley
T A
TA
Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan.
Coughenour
L L
LL
Myers
S L
SL
Shih
Y H
YH
Courtland
G G
GG
Berghoff
W
W
Stewart
S F
SF
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects*; D003024:Clozapine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D006220:Haloperidol / Q000378:metabolism / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D011388:Prolactin / Q000097:blood; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism
D014150:Antipsychotic Agents; D007093:Imidazoles; D018377:Neurotransmitter Agents; D011743:Pyrimidines; D012701:Serotonin; D013134:Spiperone; C061283:CI 943; D011388:Prolactin; D003024:Clozapine; D006220:Haloperidol; D001058:Apomorphine; D004298:Dopamine; D009638:Norepinephrine