Selective antidopaminergic effects of S(+)N-n-propylnoraporphines in limbic versus extrapyramidal sites in rat brain: comparisons with typical and atypical antipsychotic agents

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Abstract
Dopamine (DA), injected unilaterally into rat forebrain after pretreatment with a monoamine oxidase inhibitor, equipotently induced locomotor arousal when placed in the nucleus accumbens septi (a limbic site) and contralateral deviation of the head when placed in the corpus striatum (an extrapyramidal target); testing was done with an ED50 dose of DA (16 µg). Systemic injections (IP) of the representative typical neuroleptic haloperidol showed high potency and minorstriatal selectivity against the behavioral effects of intracerebral DA [accumbens ID50=0.090, striatum=0.027 mg/kg (0.24 and 0.072 µmol/kg); ID50 ratio=3.3, favoring striatum]. The atypical antipsychotic agent clozapine was less potent against DA in both brain regions but, paradoxically, showed ever greater striatal selectivity [ID50=12 and 1.4 mg/kg (37 and 4.2 µmol/kg); ratio=8.8, favoring striatum], while its analog, the piperazinyl-dibenzothiazepine ICI-204,636 showed intermediate potency and the lowest striatal selectivity of these three neuroleptic agents [ID50=1.8 and 0.88 mg/kg (4.1 and 2.0 µmol/kg); ratio=2.1]. In striking contrast, the S(+) isomers of N-n-propylnorapomorphine, its orally active 10,11-methylenedioxy prodrug derivative, and its 11-monohydroxy analog all induced potent antagonism oflimbic DA but had little effect on extrapyramidal injections of DA except at high systemic doses [ID50, accumbens=0.18–0.52, striatal=10–15 mg/kg (0.50–1.6 and 29–42 µmol/kg); regional ID50 ratios=18–69, favoring accumbens]. The S(+)aporphines showed limbic potency similar to that of haloperidol and 25–73 times greater than that of clozapine. The S(+)11-OH-aporphine was 2.7–3.1 times more potent (on a molar dose basis) than the other aporphines against DA in accumbens, and 0.5, 8 and 73 times as potent as haloperidol, ICI-204,636 and clozapine. The significantly dissimilar slopes of dose-effect functions for the two groups of agents suggest that different actions may mediate the limbic effects of the aporphines and the neuroleptics tested. ICI-204-636 appears to be pharmacologically similar to clozapine, but 2.1 times more potents versus limbic-DA. The S(+)N-n-propylnoraporphines are potent and regionally highly selectivelimbic DA antagonists and S(+)-11-hydroxy-N-n-propylnoraporphine is orally active. These and other aporphine analogs are proposed for development as potential atypical antipsychotic agents with a low risk of extrapyramidal neurological side effects, and the present methods are proposed for predicting relative limbic versus extrapyramidal antidopaminergic activity.