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.

Abstract

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. 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. 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 t1/2 = 4.1 h, significantly longer than t1/2 = 2.9 h after treatment with l-DOPA, consistent with the 6-OHDA results. 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.