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DopAmide: Novel, Water‐Soluble, Slow‐Release l ‐dihydroxyphenylalanine ( l ‐DOPA) Precursor Moderates l ‐DOPA Conversion to Dopamine and Generates a Sustained Level of Dopamine at Dopaminergic Neurons
Author(s) -
Atlas Daphne
Publication year - 2016
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.12518
Subject(s) - dopamine , dopaminergic , levodopa , chemistry , aromatic l amino acid decarboxylase , bioavailability , pharmacology , dihydroxyphenylalanine , prodrug , decarboxylation , parkinson's disease , medicine , biochemistry , catalysis , disease
Summary Background Long‐term l ‐dihydroxyphenylalanine ( l ‐ DOPA ) treatment of Parkinson's disease ( PD ) is associated with motor complications known as l ‐ DOPA ‐induced dyskinesias ( LID ) and on/off fluctuations, which are linked to unsteady pulsatile dopaminergic stimulation. Aim The objective of this study was to improve l ‐ DOPA treatment by slowing and stabilizing dopamine (DA) production in the brain and increasing water solubility to provide a rescue therapy for PD . Results We synthesized l ‐ DOPA ‐amide, a novel l ‐ DOPA precursor called DopAmide. DopAmide is water soluble and, as a prodrug, requires hydrolysis prior to decarboxylation by the aromatic l ‐amino acid decarboxylase ( EC 4.1.1.28; AAAD ). In the 6‐ OH ‐dopamine (6‐ OHDA )‐lesioned rats, DopAmide maintained steady rotations for up to 4 h compared with 2 h by l ‐ DOPA , suggesting that this rate‐limiting step generated a sustained level of DA at dopaminergic neurons. Pharmacokinetic studies showed elimination half‐life of l ‐ DOPA in the plasma after DopAmide treatment of t 1/2 = 4.1 h, significantly longer than t 1/2 = 2.9 h after treatment with l ‐ DOPA , consistent with the 6‐ OHDA results. Conclusions The slow conversion of DopAmide to l ‐ DOPA provides a sustained level of DA in the dopaminergic cells, shown by the long 6‐ OHDA steady rotations. The water solubility and improved bioavailability may help reduce medication frequency associated with l ‐ DOPA treatment of PD . Sustained levels of DA might lower the super‐sensitization of DA signaling and potentially attenuate l ‐ DOPA adverse effects.

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