title: Deuterium substitutions in the L-DOPA molecule improve its anti-akinetic potency without increasing dyskinesias.
abstract: Treatment of Parkinson's disease is complicated by a high incidence of L-DOPA-induced dyskinesias (LID). Strategies to prevent the development of LID aim at providing more stable dopaminergic stimulation. We have previously shown that deuterium substitutions in the L-DOPA molecule (D3-L-DOPA) yield dopamine that appears more resistant to enzymatic breakdown. We here investigated the effects of D3-L-DOPA on motor performance and development of dyskinesias in a rodent model of Parkinson's disease. Through acute experiments, monitoring rotational behavior, dose-effect curves were established for D3-L-DOPA and L-DOPA. The equipotent dose of D3-L-DOPA was estimated to be 60% of L-DOPA. Subsequently, animals were treated with either the equipotent dose of D3-L-DOPA (5 mg/kg), the equivalent dose of D3-L-DOPA (8 mg/kg), L-DOPA (8 mg/kg) or vehicle. The equivalent dose of D3-L-DOPA produced superior anti-akinetic effects compared to L-DOPA in the cylinder test (p<0.05), whereas the equipotent dose of D3-L-DOPA produced an anti-akinetic effect similar to L-DOPA. Dyskinesias developed to the same degree in the groups treated with equivalent doses of D3-L-DOPA and L-DOPA. The equipotent dose of D3-L-DOPA induced fewer dyskinesias than L-DOPA (p<0.05). In conclusion, our study provides evidence for improved potency and reduced side-effects of L-DOPA by deuterium substitutions in the molecule. These results are of clinical interest since the occurrence of LID is related to the total L-DOPA dose administered. D3-L-DOPA may thus represent a novel strategy to reduce the total dose requirement and yet achieve an effective control of parkinsonian symptoms.
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden. Torun.Malmlof@ki.se
authors.forename: Torun
authors.initials: T
authors.lastname: Malmlöf
authors.forename: Daniella
authors.initials: D
authors.lastname: Rylander
authors.forename: Rudolf-Giesbert
authors.initials: RG
authors.lastname: Alken
authors.forename: Frank
authors.initials: F
authors.lastname: Schneider
authors.forename: Torgny H
authors.initials: TH
authors.lastname: Svensson
authors.forename: M Angela
authors.initials: MA
authors.lastname: Cenci
authors.forename: Björn
authors.initials: B
authors.lastname: Schilström
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced; D007150:Immunohistochemistry; D007980:Levodopa / Q000737:chemistry* / Q000627:therapeutic use*; D009043:Motor Activity / Q000187:drug effects*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D045442:Rotarod Performance Test; D018709:Statistics, Nonparametric; D016896:Treatment Outcome; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase