Neuroleptics 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). 

Figure 2.3 Dextromethorphan 6, the unnatural enantiomer of a narcotic morphine analog, is an antitussive drug. The antidiarrhea drug loperamide 7 and the neuroleptic drug haloperidol 8 also resulted from structural modification of morphine. The morphine antagonist nalorphine 9 differs from the opioid agonist morphine 3 (Figure 2.2) only by having an N-allyl group instead of the N-methyl group.

QSRR analysis of HPLC data determined on an immobilized human serum albumin (HSA) column helped to propose the topography of two binding sites of different affinity to benzodiazepine enantiomers 1143.163). Also, the mechanism of interaction of phenothiazine neuroleptics with melanin was rationalized by means of QSRR analysis of HPLC retention data [132,164]. Another QSRR study concerned the interactions of drugs with immobilized keratin and collagen [ 165). 

Comparison of the racemate and the two enantiomers of a fiuoro anaiogues of the tricyclic neuroleptic... 

Structure-activity studies of l-piperazino-3-phenylindanes led to the development of the potent and long-lasting neuroleptic, tefludazine (7a). The cis-isomer of tefludazine has 1/1000 the activity of 71 in blocking methylphenidate-induced stereotypy in mice. One member of the tefludazine series, the bisfluoro derivative (7b) was resolved the antidopaminergic activities resided in the (+)-enantiomer. The (-)-enantiomer, however, proved to be an active uptake inhibitor of... 

Classical resolutions are not restricted to racemic compounds containing tetrahedral chiral centres, a point exemplified by Phillips et al. [18] in work directed at clozapine analogues as potential neuroleptic agents. The 5//-di-benzo[a, f]cycloheptene (7), which exists as configurational enantiomers by virtue of planar chirality [19], was resolved using (215,35)- and (2/ ,3/ )-di-p-toluoyltartaric acids (Scheme 5.5)... 

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