Synthesis and evaluation of dopaminergic prodrugs designed for transdermal iontophoretic drug delivery. Highly water-soluble amino acid ester prodrugs applicable for the treatment of Parkinson’s disease

PhD ceremony: Mr. J. de Graan, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Synthesis and evaluation of dopaminergic prodrugs designed for transdermal iontophoretic drug delivery. Highly water-soluble amino acid ester prodrugs applicable for the treatment of Parkinson’s disease

Promotor(s): prof. B.H.C. Westerink

Faculty: Mathematics and Natural Sciences

Dopamine agonists are used as pharmacotherapy for patients with Parkinson's disease. In his thesis Jeroen de Graan describes the preparation and evaluation of highly water-soluble derivatives of the dopamine agonist 5-OH-DPAT. These derivatives are chemically coupled compounds of 5-OH-DPAT with other molecules, i.e. amino acids. In pharmacy these compounds are named prodrugs. A prodrug is a non-pharmacologically active compound which will release the active drug after conversion in the body.

De Graan's research has led to several findings. First, highly water-soluble prodrugs were synthesized which showed sufficient stability while in solution in the iontophoretic patch (sufficient sustainability), but released the drug on entry in the bloodstream. Second, by coupling 5-OH-DPAT to dipeptides (two combined amino acids) he obtained even more stable prodrugs. Third, 5-OH-DPAT could be administered in a controlled manner, which would facilitate the development of a feedback system. Finally, he found that the iontophoretic delivery of a highly water-soluble prodrug of 5-OH-DPAT led to a prolongation of the pharmacological effect in comparison to 5-OH-DPAT itself.

These results show that the application of prodrugs can be advantageous for the administration of dopamine agonists and other drugs by transdermal iontophoresis. Further research of this pharmaceutical dosage form could eventually lead to a new pharmacotherapy of patients with Parkinson's disease.