CI-943 ((±)-CI-943)

Antipsychotics and neuropeptides: the atypical profile of CI-943 and its relationship to neurotensin

CI-943 is a new drug candidate with antipsychotic-like activity in a variety of behavioural tests in rodents and primates, but without any affinity for brain dopamine receptors. CI-943 does not cause dystonia in monkeys, a predictive symptom of extrapyramidal side effects (EPS). Its mechanism of action remains unclear. Neurotensin (NT) concentration in nucleus accumbens and caudate is increased by CI-943; this may be associated with its antipsychotic effect. Indeed various observations suggest that the clinical action of antipsychotic drugs may at least be partially mediated by some neuropeptides. Various actions of neurotensin are reviewed. The hypothesis on the role of neurotensin represents a new strategy in the development of pharmacological tools for the treatment of schizophrenia.

CI-943, a potential antipsychotic agent. I. Preclinical behavioral effects

CI-943 (8-ethyl-7,8-dihydro-1,3,5-trimethyl-1H-imidazo[1,2-c] pyrazolo[3,4-e]-pyrimidine) is a novel agent that is chemically unrelated to available antipsychotics and is not a dopamine receptor antagonist. Like available antipsychotics, CI-943 reduces spontaneous locomotion in mice and rats and inhibits compulsive cage climbing induced by apomorphine in mice at doses that do not produce ataxia. However, CI-943 enhances rather than inhibits the locomotor stimulant effects of d-amphetamine in mice and rats. Unlike dopamine antagonists, CI-943 does not affect stereotypy caused by apomorphine or amphetamine in rats. CI-943 displays an antipsychotic-like profile in conditioned avoidance tests, inhibiting one-way avoidance in rats at doses that do not impair escape and inhibiting continuous avoidance in rats and squirrel monkeys at doses that do not impair shock termination responding. Although high doses of CI-943 produce dystonic movements in haloperidol-sensitized monkeys, CI-943 differs from dopamine antagonists that produce extrapyramidal dysfunction in humans in that doses of CI-943 that are sufficient to inhibit avoidance responding in monkeys do not produce extrapyramidal dysfunction. Unlike dopamine antagonists that produce tardive dyskinesia, CI-943 administered repeatedly at high doses does not produce behavioral supersensitivity to dopamine agonists in rats. These results demonstrate that CI-943 resembles available antipsychotics in some preclinical behavioral tests commonly used to predict antipsychotic efficacy but differs from dopamine antagonists in tests predictive of dopamine receptor antagonism and antipsychotic-induced neurological dysfunction.

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.

CI-943, a potential antipsychotic agent. III. Evaluation of effects on dopamine neuronal activity

CI-943 (8-ethyl-7,8-dihydro-1,3,5-trimethyl-1H-imidazo[1,2- c]pyrazolo[3,4-e]pyrimidine) has been identified as a novel potential antipsychotic agent that does not bind to dopamine (DA) receptors. In the present studies, the effects of acute and chronic administration of CI-943 on the electrophysiological activity of A9 and A10 DA neurons were assessed and compared to the effects of DA antagonist antipsychotic drugs. Acute administration of CI-943 did not increase the base-line firing rate (10-20 mg/kg i.p.), did not increase the number of spontaneously active DA neurons (40 mg/kg p.o.) and did not antagonize the effects of apomorphine or amphetamine on A9 or A10 DA neurons (20-40 mg/kg i.p.). A high dose of CI-943 (40 mg/kg i.p.) decreased the firing rate of A9 and A10 DA neurons, an effect that was not antagonized by haloperidol. In contrast, haloperidol increased the base-line firing rate (0.5 mg/kg i.p.), increased the number of spontaneously active DA neurons (0.5 mg/kg p.o.) and antagonized the effects of apomorphine and d-amphetamine on A9 and A10 DA neurons (0.1 mg/kg i.p.). Repeated (21 days) administration of CI-943 (36 mg/kg/day p.o.) did not alter the number of spontaneously active A9 DA neurons but increased the number of active A10 DA neurons. In contrast, repeated administration of haloperidol (0.4 mg/kg/day p.o.) decreased the number of spontaneously active DA neurons in A9 and A10, whereas repeated administration of clozapine (19 mg/kg/day p.o.) decreased the number of active A10 DA neurons but increased the number of active A9 DA neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of CI-943, a potential antipsychotic drug, and haloperidol on regional brain neurotensin concentrations

Treatment with efficacious antipsychotic drugs such as haloperidol increases the concentrations of neurotensin (NT) in the nucleus accumbens and caudate nucleus of the rat. These increases in NT concentrations may be associated with the therapeutic and/or side effects of these drugs. CI-943, a novel compound without appreciable affinity for dopamine-binding sites, produces behavioral effects in animals, which suggest that it may possess antipsychotic activity. This study evaluated the effects of subchronic treatment (3 weeks) with CI-943 or haloperidol on regional brain NT concentrations in rats. Haloperidol treatment (1 mg/kg) produced significant increases in the concentrations of NT in the nucleus accumbens and caudate nucleus but not in the other brain regions studied. Like haloperidol, CI-943 (40 mg/kg) increased NT concentrations in the nucleus accumbens and caudate but differed in that CI-943 produced significantly greater increases in NT concentration in the caudate than haloperidol and also increased NT content in the substantia nigra/ventral tegmental area and hypothalamus. The regional specificity of the NT alterations produced by chronic treatment with CI-943, a nondopamine receptor ligand, was similar to that previously reported after treatment with multiple doses of methamphetamine.