Diester derivatives as apomorphine prodrugs

Area of Science:

• Pharmacology
• Medicinal Chemistry
• Neuroscience

Background:

• Apomorphine is a dopamine agonist used clinically.
• Developing effective prodrugs can improve drug delivery and duration of action.
• Understanding prodrug metabolism is crucial for therapeutic efficacy.

Purpose of the Study:

• To synthesize apomorphine diesters as potential prodrugs.
• To evaluate the in vivo conversion of these diesters to apomorphine.
• To assess the pharmacological effects and duration of action of the synthesized prodrugs.

Main Methods:

• Synthesis of apomorphine diester series.
• In vivo administration and detection of apomorphine in brain tissue.
• Assessment of stereotyped gnawing behavior and unilateral rotation.
• In vitro hydrolysis assays using liver extracts.

Main Results:

• All synthesized diesters were converted in vivo to free apomorphine.
• Apomorphine diesters induced behavioral effects similar to apomorphine but with prolonged action.
• Duration of action correlated with ester substituent size and inversely with hydrolysis rate.
• Hydrolysis rate decreased with increasing steric hindrance.

Conclusions:

• Apomorphine diesters function effectively as prodrugs.
• The prolonged duration of action is attributed to reduced hydrolysis rates.
• Steric hindrance at acyl carbon atoms influences ester hydrolysis and prolongs efficacy.