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Molecules 2018, 23(1), 40; https://doi.org/10.3390/molecules23010040

Dopamine and Levodopa Prodrugs for the Treatment of Parkinson’s Disease

Department of Bioorganic & Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Quds University, Jerusalem P.O. Box 20002, Palestine
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Received: 4 December 2017 / Revised: 18 December 2017 / Accepted: 20 December 2017 / Published: 25 December 2017
(This article belongs to the Section Medicinal Chemistry)
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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. View Full-Text
Keywords: dopamine; levodopa; prodrug; Parkinson’s disease; blood brain barrier dopamine; levodopa; prodrug; Parkinson’s disease; blood brain barrier
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Haddad, F.; Sawalha, M.; Khawaja, Y.; Najjar, A.; Karaman, R. Dopamine and Levodopa Prodrugs for the Treatment of Parkinson’s Disease. Molecules 2018, 23, 40.

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