Stereoselective actions of substituted benzamide drugs on cerebral dopamine mechanisms

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Abstract
Apomorphine-induced locomotor activity in reserpine-pretreated mice was antagonized by pretreatment with (-)-sulpiride and (-)-sultopride. The (+)-enantiomers were inactive. Apomorphine- and amphetamine-induced stereotyped behaviour in rats were antagonized by (-)-sultopride but not by the (+)-enantiomer. Neither enantiomer of sulpiride prevented the onset of the stereotyped response. Both (-)-sulpiride and (-)-sultopride induced increases in striatal and mesolimbic HVA and DOPAC concentrations; (+)-sultopride elevated striatal and mesolimbic DOPAC concentrations but not HVA, while (+)-sulpiride had no effect on HVA or DOPAC in either area. Dopamine concentrations were reduced by the enantiomers of sultopride but not by sulpiride. Low concentrations (10−9 −10−66 M) of the (-)-enantiomers of both drugs displaced [3 H]spiperone from its specific binding site in rat striatal preparations, but the (+)-enantiomers were 40 and 100 times less active. However, neither enantiomer of either drug anatagonized the dopamine-induced stimulation of adenylate cyclase in rat striatal preparations. The data suggest that the central pharmacological activity of sulpiride and sultopride resides in the (-)-enantiomers and that this activity occurs at cerebral dopamine receptors not dependent on adenylate cyclase for functional activity.