Substituted and unsubstituted 10,11-methylenedioxy derivatives of
apomorphine (APO) or its N-propyl congener (NPA) were synthesized and evaluated for their ability to alter motor activity or to induce stereotyped behavior in the rat. Of these, (-)10,11-methylenedioxy-N-n-propylnoraporphine hydrochloride (
MDO-NPA) was the most active, and the only compound which was found to be active after
oral administration. Also,
MDO-NPA was more potent than NPA or APO in producing stereotypy, but large doses of these three
aporphines were equipotent in stimulating motor activity. The duration of action of
MDO-NPA exceeded that of NPA and APO, and increased with increasing doses. The effects of
MDO-NPA on general activity were biphasic: larger doses stimulated activity: smaller doses markedly inhibited it and induced
catalepsy.
Catalepsy did not occur with NPA or APO and their motor-inhibitory effects were apparent only in aroused rats. The stereotypic effects of
MDO-NPA were blocked by small doses of
haloperidol, but not by large doses of
reserpine. The effects due to large or small doses of
MDO-NPA were also blocked by a microsomal
enzyme inhibitor which did not interfere with the actions of NPA. These results suggest that
MDO-NPA is a long-acting, orally effective
prodrug of NPA with depot properties and dose-dependent agonistic and antagonistic interactions with central
dopamine-mediated systems.