Dopamine and Levodopa Prodrugs for the Treatment of Parkinson’s Disease
Date
2017-12-25
Authors
Haddad, Fatma
Sawalha, Maryam
Khawaja, Yahya
Najjar, Anas
Karaman, Rafik
Journal Title
Journal ISSN
Volume Title
Publisher
MDPI
Abstract
Background: Parkinson’s disease is an aggressive and progressive neurodegenerative
disorder that depletes dopamine (DA) in the central nervous system. Dopamine replacement
therapy, mainly through actual dopamine and its original prodrug L-dopa (LD), faces many
challenges such as poor blood brain barrier penetration and decreased response to therapy with time.
Methods: The prodrugs described herein are ester, amide, dimeric amide, carrier-mediated, peptide
transport-mediated, cyclic, chemical delivery systems and enzyme-models prodrugs designed and
made by chemical means, and their bioavailability was studied in animals. Results: A promising
ester prodrug for intranasal delivery has been developed. LD methyl ester is currently in Phase
III clinical trials. A series of amide prodrugs were synthesized with better stability than ester
prodrugs. Both amide and dimeric amide prodrugs offer enhanced blood brain barrier (BBB)
penetration and better pharmacokinetics. Attaching LD to sugars has been used to exploit glucose
transport mechanisms into the brain. Conclusions: Till now, no DA prodrug has reached the
pharmaceutical market, nevertheless, the future of utilizing prodrugs for the treatment of PD seems to
be bright. For instance, LD ester prodrugs have demonstrated an adequate intranasal delivery of LD,
thus enabling the absorption of therapeutic agents to the brain. Most of the amide, cyclic, peptidyl or
chemical delivery systems of DA prodrugs demonstrated enhanced pharmacokinetic properties.
Description
Keywords
dopamine , levodopa , prodrug , Parkinson’s disease , blood brain barrier