title: 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: 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.
  
  
  OBJECTIVE
  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 t1/2 = 4.1 h, significantly longer than t1/2 = 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.
authors: Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors: Daphne
authors: D
authors: Atlas
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology* / Q000627:therapeutic use; D065105:Aromatic Amino Acid Decarboxylase Inhibitors / Q000494:pharmacology; D002230:Carbidopa / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D007980:Levodopa / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D012399:Rotation; D013565:Sympatholytics / Q000633:toxicity; D013997:Time Factors
chemical_list: D000978:Antiparkinson Agents; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D000697:Central Nervous System Stimulants; D013565:Sympatholytics; D007980:Levodopa; D016627:Oxidopamine; D000661:Amphetamine; D002230:Carbidopa; D004298:Dopamine
keywords: Dyskinesia; Levodopa; On\Off fluctuations; Parkinson's disease; l-Dihydroxyphenylalanine-induced dyskinesia