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

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.

Keywords: Parkinson’s disease; blood brain barrier; dopamine; levodopa; prodrug.

Scheme 1

Dopamine synthesis pathway.

Figure 1

Select peripheral actions of dopamine.

Figure 2

Chemical structures of LD ester prodrugs, 1–10.

Figure 3

Chemical structures of lipophilic 3,4-O-diester prodrugs of DA, 11–15.

Figure 4

Chemical structures of general amide prodrugs (16) and (S)-4-(2-acetamido-3-ethoxy-3-oxopropyl)-1,2-phenylene diacetate (17).

Figure 5

Chemical structures of a synthetic series of amide prodrugs, 18–33.

Figure 6

Chemical structures of substituted 2-phenyl-imidazopyridine-3-acetic acid amide prodrugs of LD.

Figure 7

Chemical structures of dimeric amide prodrugs, 42–50.

Figure 7

Chemical structures of dimeric amide prodrugs, 42–50.

Figure 8

Glycosyl DA derivatives, 51–63.

Figure 9

Chemical structures of glycosuccinyl-derivatives of DA, 64 and 65.

Figure 10

Structure of 2-amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenylpropionamide (DA-PHEN), 66.

Figure 11

Glutathione conjugated prodrug of dopamine, 67.

Scheme 2

Activation mechanism of carboxylic acid-thiazolium prodrugs of LD.

Figure 12

Chemical structures of carboxylic acid-thiazolium prodrugs of LD, 68–71.

Figure 13

Chemical structures of cyclic prodrugs of LD, 73–75.

Figure 14

Chemical structures of DA prodrugs 76 and 77.