title: L-745,870 reduces L-DOPA-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease.
abstract: L-DOPA-induced dyskinesia remains an unmet challenge in the treatment of Parkinson's disease (PD). Here, we investigate the potential antidyskinetic efficacy of 3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H-pyrrolo[2,3-b]pyridine (L-745,870), a potent and selective dopamine D(4) receptor antagonist with a good toxicology profile and an excellent safety and tolerability record in phase I/II clinical studies, for non-PD indications. Six macaques were rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. After induction of stable and marked dyskinesia, animals were administered acute challenges of L-745,870 in combination with L-DOPA. To guarantee D(4) selectivity at the doses used in the study, we determined the plasma, cerebrospinal fluid, and brain levels of L-745,870. Coadministration of L-745,870 (1 mg/kg) and L-DOPA significantly reduced the severity of dyskinesia, by up to 59%, in comparison with L-DOPA alone (P < 0.01). L-745,870 had no effect on the duration of antiparkinsonian benefit (ON-time) (P > 0.05). However, L-745,870 (1 mg/kg) significantly increased the duration of ON-time without disabling dyskinesia (+204%; P < 0.001) and decreased duration of ON-time with disabling dyskinesia compared with L-DOPA alone (-56%; P < 0.01). Brain levels of L-745,870 (∼600 ng/g) were within the range at which L-745,870 provides selective D(4) receptor antagonism. Plasma levels were comparable with those demonstrated to be well tolerated in human studies. These data suggest that selective D(4) receptor antagonists represent a potential therapeutic approach for L-DOPA-induced dyskinesia. It is noteworthy that L-745,870 has already undergone significant clinical development, has an excellent profile for a therapeutic candidate, and could be advanced rapidly to phase IIa clinical studies for dyskinesia in PD.
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Huot
authors.forename: Tom H
authors.initials: TH
authors.lastname: Johnston
authors.forename: James B
authors.initials: JB
authors.lastname: Koprich
authors.forename: Ahmed
authors.initials: A
authors.lastname: Aman
authors.forename: Susan H
authors.initials: SH
authors.lastname: Fox
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Brotchie
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D000978:Antiparkinson Agents / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D020820:Dyskinesias / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D007980:Levodopa / Q000494:pharmacology*; D008251:Macaca; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010300:Parkinson Disease / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000378:metabolism; D011725:Pyridines / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000494:pharmacology*; D011758:Pyrroles / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000494:pharmacology*; D050638:Receptors, Dopamine D4 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C099630:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine; D000978:Antiparkinson Agents; D011725:Pyridines; D011758:Pyrroles; D050638:Receptors, Dopamine D4; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine