title: The highly-selective 5-HT(1A) agonist F15599 reduces L-DOPA-induced dyskinesia without compromising anti-parkinsonian benefits in the MPTP-lesioned macaque.
abstract: L-3,4-dihydroxyphenylalanine (L-DOPA) is the most effective anti-parkinsonian agent available, but upon chronic administration, patients with Parkinson's disease (PD) experience abnormal involuntary movements, dyskinesia. Modulation of serotonin 1A (5-HT1A) receptors is regarded as an effective way to alleviate dyskinesia, yet this approach has been marred by a reduction of the therapeutic effectiveness of L-DOPA. We hypothesised that highly-selective 5-HT1A stimulation might be a way to alleviate dyskinesia without compromising L-DOPA anti-parkinsonian action. F15599 (also known as NLX-101) is a highly-selective 5-HT1A agonist that displays over 1000 × selectivity over off-target receptors. Seven cynomolgus macaques were administered MPTP and developed severe parkinsonism. Following chronic administration of L-DOPA, they developed severe and reproducible dyskinesia. F15599 (0.003, 0.01, 0.03 and 0.1 mg/kg) or vehicle was administered in combination with L-DOPA and its effect on dyskinesia and L-DOPA anti-parkinsonian was assessed. In combination with L-DOPA, F15599 (0.1 mg/kg) reduced the severity of peak-dose dyskinesia, by ≈45% (P < 0.001), compared to L-DOPA alone. F15599 (any dose) had no effect on duration of on-time or motor activity counts compared to L-DOPA alone. F15599 at 0.03 and 0.1 mg/kg significantly reduced duration of on-time with disabling dyskinesia (by ≈49% and ≈71%, P < 0.05 and P < 0.001, respectively). These results suggest that F15599, a highly-selective 5-HT1A receptor agonist, alleviates dyskinesia without exerting a deleterious effect on L-DOPA anti-parkinsonian action.
authors.affiliation: Toronto Western Research Institute, University Health Network, 60 Leonard Ave., Toronto, ON, Canada; Division of Neurology, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, 399 Bathurst Street, Toronto, ON, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Huot
authors.affiliation: Toronto Western Research Institute, University Health Network, 60 Leonard Ave., Toronto, ON, Canada.
authors.forename: Tom H
authors.initials: TH
authors.lastname: Johnston
authors.affiliation: Toronto Western Research Institute, University Health Network, 60 Leonard Ave., Toronto, ON, Canada; Division of Neurology, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, 399 Bathurst Street, Toronto, ON, Canada.
authors.forename: Susan H
authors.initials: SH
authors.lastname: Fox
authors.affiliation: Neurolixis Inc., Dana Point, CA, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Newman-Tancredi
authors.affiliation: Toronto Western Research Institute, University Health Network, 60 Leonard Ave., Toronto, ON, Canada. Electronic address: j.brotchie@atuka.com.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Brotchie
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D007980:Levodopa / Q000009:adverse effects / Q000494:pharmacology*; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000503:physiopathology; D008252:Macaca fascicularis; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D012720:Severity of Illness Index
chemical_list: C524188:3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methylpyrimidin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone; D000978:Antiparkinson Agents; D010880:Piperidines; D011743:Pyrimidines; D058825:Serotonin 5-HT1 Receptor Agonists; D007980:Levodopa
keywords: Dyskinesia; F15599; L-DOPA; MPTP-lesioned macaque; On-time