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

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... OPA 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.