Sulpiride enantiomers

Die specificity of the dopamine receptor was further studied with a series of dopaminergic antagonists of well known pharmacological activity. The 30-40% inhibitory effect of 10 nM dopamine was completely reversed by the addition of increasing concentrations of the potent neuroleptics (+)butaclamol (Kp = 1.5 nM) and (-)sulpiride (Kp = 0.5 nM) while their pharmacologically weak enantiomers (-)butaclamol and (+)sulpiride were 86 and 167 times less potent, respectively. The neuroleptics spiroperidol, thioproperazine, domperidone, haloperidol, fluphenazine and pimozide completely reversed the inhibitory effect of dopamine at low Kp values ranging from 0.02 to 0.8 nM (41). 

Qualitative differences have also been observed in relative DA, and DA- activity of several antagonists. The differences are strikingly demonstrated with the enantiomers of sulpiride. (S)-sulpiride is much more active than (R)-sulpiride as a DA antagonist whereas, (R)-sulpiride is slightly more active tnan (S)-sulpiride as a DA antagonist (11). 

A comprehensive reivew of studies of the action of DA, agonists and antagonists in isolated blood vessels and organs was recently published (31). In general, there is good correlation between in vivo and in vitro data with isolated canine blood vessels. However, exceptions have been reported with isolated preparations of other species. The major differences are that sulpiride and its enantiomers appear to be much more potent in vivo than in vitro. Another discrepancy is that bromocriptine, which is inactive on DA, receptors in vivo, has been shown to cause DA-like vasodilation of the isolated perfused rat kidney and relaxation of rabbit mesenteric artery strips. 

An immediate improvement in the drug properties could be obtained by the replacement of the sulfamido group with a more lipophilic group such as halogen. Compound (70) inhibited apomorphine-induced stereotypy in rats at a 30-fold lower dose than sulpiride (330). Whereas the racemic 2,6-di-methoxy derivative (71) was equipotent with sulpiride against apomorphine mediated behaviors, the S-enantiomer of the 3-bromo-2,6-dimethoxy derivative (remoxipride) (72) closely resembled haloperidol in its ability to block apomorphine-induced hyperactivity. The sevenfold ratio of stereotypy to hyperactivity for remoxipride suggested a low propensity to produce EPS in the clinic. Remoxipride was briefly used in clinical practice, but the development of aplastic anemia in a minority of patients led to its eventual withdrawal (331). 

Levosulpiride is the (-) enantiomer of sulpiride, an antiemetic, antidyspeptic, and antipsychotic drug. However, levosulpiride is a more potent antiemetic compound than sulpiride. Levosulpiride (50 to 300 mg/day) is effective in depressive and somatoform disorders, as well as in the treatment of negative symptoms in schizophrenic patients. 

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