Butaclamol enantiomers

Aboul-Enein, H.Y. and Hefnawy, M.M., Chiral analysis of butaclamol enantiomers in human plasma by HPLC using a macrocychc antibiotic (vancomycin) chiral stationary phase and sohd phase extraction. Chirality, 16, 147, 2004. 

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). 

Butaclamol exerts its effects by blockade of central dopamine receptors (DAR), and is unique in that it was the first DAR antagonist wherein all the activity was due to one enantiomer (1 3, 14). Resolution studies (14) had demonstrated that (+)-butaclamol, I,... 

Thus, the enantiomers of butaclamol are differentiated by the DAR with absolute enantiospecificity. Apart from this attribute of butaclamol, another unique feature is the restricted conformational mobility of its nucleus. There exists another DAR ligand, the agonist (-)-apomorphine, II, (1 7), which also possesses a semi-rigid nucleus and for which the DAR is equally enantio-specific (18). 

This receptor representation also accounts for the chirality of the receptor. Thus, if the pharmacologically inactive (-)-enantiomer of butaclamol is oriented to the receptor with its ring A bound to the 8-region of the phenyl ring binding site, it requires the existence of a nitrogen atom location site at position D1 (+3.2 X,+0.9 Z). It would appear that either no such site exists at D, or, that the molecule would have to occupy "disallowed" space in the +Z octants of the coordinate system in which the receptor is oriented. 

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