Diester derivatives as apomorphine prodrugs

A series of diesters of apomorphine was synthesized to serve as prodrugs. They were converted in vivo to free apomorphine, which could be detected in the brain. Stereotyped gnawing behavior and unilateral rotation similar to that produced by apomorphine were induced by all of the diesters but the time course of action of the latter was prolonged. The duration of action generally increased with the size of the ester substituent and appeared to correlate inversely with the rate of hydrolysis of the esters by liver extracts. It is concluded that the diesters serve as prodrugs of apomorphine and their prolonged duration is partly explained by a decreasing rate of hydrolysis attributable to increased steric hindrance at the acyl carbon atoms.