S(+)methylenedioxy-N-n-propylnoraporphine: an orally active inhibitor of dopamine selective for rat limbic system.
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.
D000284:Administration, Oral; D000818:Animals; D001058:Apomorphine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D001060:Aporphines / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D008032:Limbic System / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism
D001060:Aporphines; D011954:Receptors, Dopamine; C033829:10,11-methylenedioxy-N-propylnoraporphine; D011335:Proadifen; D001058:Apomorphine; D004298:Dopamine