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.
Highlights
Dopamine (DA) is a natural neurotransmitter and neurohormone that exerts its action by binding to five DA receptors in the brain, D1–5 [1]
DA production represents the first steps in catecholamine synthesis and starts with phenylalanine which is hydroxylated to tyrosine, again to levodopa (LD)
Administering external dopamine to Parkinson’s disease (PD) patients as treatment is limited, as dopamine is a water-soluble hydrophilic drug that does not satisfy the characteristics of a substance that can enter the brain by blood brain barrier (BBB) penetration [1,10,11]
Summary
The prodrugs described 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. 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). LD ester prodrugs have demonstrated an adequate intranasal delivery of LD, enabling the absorption of therapeutic agents to the brain. Cyclic, peptidyl or chemical delivery systems of DA prodrugs demonstrated enhanced pharmacokinetic properties
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