Aporphines. 48. Enantioselectivity of (R)-(-)- and (S)-(+)-N-n-propylnorapomorphine on dopamine receptors

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Abstract
The enantiomers [(S)-(+) and (R)-(-)] of N-n-propylnorapomorphine (NPA) were synthesized. (R)-NPA was obtained by the acid-catalyzed rearrangement of N-n-propylnormorphine. (R)-NPA also was converted to (RS)-N-n-propylnorapomorphine dimethyl ether by dehydrogenation of the 10,11-O,O''-dimethyl ether of (R)-NPA with 10% palladium on carbon in acetonitrile, followed by reduction with sodium cyanoborohydride under acidic conditions. Alternatively, (RS)-NPA 10,11-O,O''-dimethyl ether was obtained via total synthesis. (+)-Dibenzoyl-D-tartaric acid was used to resolve (RS)-NPA dimethyl ether. Ether cleavage gave (S)-NPA isolated as the hydrochloride salt in greater than 99.9% enantiomeric purity, as determined by circular dichroism (CD) spectra. The pharmacological activities of (S)- and (R)-NPA was evaluated with sub-nmol concentrations of 3H-labeled apomorphine (APO), ADTN [2-amino-6,7-dihydroxytetrahydro-naphthalene], and spiroperidol (SPR) for competition for binding to a membrane-rich subsynaptosomal fraction of calf caudate nucleus. IC50 [median inhibitory concentration] (nM) values for (R)-NPA vs. (S)-NPA were as follows: [3H]APO, 2.5 vs. 66; and [3H]ADTN, 2.0 vs. 60; [3H]SPR, 174 vs. 1400. The efficacy of (R)- and (S)-NPA in stimulating dopamine-sensitive adenylate cyclase from both homogenates of rat corpus striatum and species of intact carp retina was also evaluated. Three behavioral effects in the rat (stereotyped behavior, sedation and catalepsy) were also examined. Only (R)-NPA induced stereotypy; (S)-NPA failed to antagonize this action of the R isomer. The effects of (R)- and (S)-NPA on adenylate cyclase agreed with the behavioral effects and radioreceptor binding assays in that the R isomer was the strongly preferred enantiomer at dopamine receptors. The S enantiomer of NPA was the weakly preferred configuration for rat liver catechol O-methyltransferase. A dopamine-receptor model accommodates the configuration of NPA and related aporphines.