S(+)methylenedioxy-N-n-propylnoraporphine: an orally active inhibitor of dopamine selective for rat limbic system

Abstract

The 10–11-methylenedioxy (MDO) derivative of S(+)N-n-propylnorapomorphine (NPA) was prepared and tested as a possible active prodrug to S(+)NPA, which we have recently found to exert in vivo activity suggestive of selective antagonism of dopamine receptors in the limbic forebrain but not the extrapyramidal basal ganglia. Like S(+)NPA, S(+)MDO-NPA inhibited the behavioral arousal induced by dopamine injected into nucleus accumbens of the rat, but not the head-turning response to dopamine injected into the corpus striatum. However, only MDO-NPA was orally active and it was somewhat longer-acting than NPA. The activity of S(+)MDO-NPA was prevented by pretreatment with the oxidase inhibitor SKF-525A. These properties are analogous to those of R(−)MDO-NPA, which we had previously reported as an orally active prodrug of the dopamine agonist R(−)NPA. Thus the methylenedioxy derivatives of the two entantiomers of NPA have properties desirable in a potentially clinically useful dopamine agonist and limbic dopamine antagonist, respectively.