Apomorphine 7?-enantiomers

Goldman ME, Kebabian JW (1984) Apomorphine enantiomers - Interactions with D-1 and D-2 dopamine receptors. Mol Pharmacol 25 18-23... 

The importance of resolution and determination of absolute configuration cannot be overemphasized. There was, in this writer s opinion, little significant progress in developing useful receptor models prior to the determination of the absolute configurations for the active enantiomers of apomorphine, I, certain N-substituted 5-hydroxy-2-amino-l,2,3,4-tetrahydronaphthalenes, and of 6,7-ADTN (X). It is very common to see structures drawn in the literature with their chiral center shown as a particular absolute configuration, for example similar to that of apomorphine. Yet, in many of these cases there is no evidence as to which isomer is active. The reversed stereochemistry for the active enantiomers of apomorphine and... 

The most useful model of the dopamine receptor(s ) has evolved largely from a concept proposed by McDermed et al. (29). This model was dependent on a knowledge of the absolute configurations for the active enantiomers of apomorphine and... 

Until very recently apomorphine (APO) was the only important chiral DA agonist whose enantiomers had been studied. The only congeneric groups of resolved agonists to be reported subsequently were 2-aminotetralins 1, 2 ). The present enantiomer study of the SK F 38393 series thus provides welcome new data for stereochemical definition of DA receptors. Moreover, the previous studies employed rather narrow choices of pharmacological models. The broader range of models presented here is therefore particularly helpful. 

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). 

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). 

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