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) -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 Ͻ 0.01). L-745,870 had no effect on the duration of antiparkinsonian benefit (ONtime) (P Ͼ 0.05). However, L-745,870 (1 mg/kg) significantly increased the duration of ON-time without disabling dyskinesia (ϩ204%; P Ͻ 0.001) and decreased duration of ON-time with disabling dyskinesia compared with L-DOPA alone (Ϫ56%; P Ͻ 0.01). Brain levels of L-745,870 (ϳ600 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.

Dyskinesias and impulse control disorders in Parkinson's disease: From pathogenesis to potential therapeutic approaches

“…Although the expression of D 4 R in striatal neurons is controversial (Fishburn et al, 1995;Matsumoto et al, 1996;Rivera et al, 2002;Suzuki et al, 1995), the selective inhibition of D 4 R reduces LID in the MPTP monkey (Huot et al, 2012a), and sarizotan, a D 4 R antagonist and 5-HT 1A receptor agonist, has been shown to reduce LID in both rat and non-human primate models (Grégoire et al, 2009;Marin et al, 2009), as well as in PD patients in clinical trials ( Bara-Jimenez et al, 2005;Olanow et al, 2004). However, this clinical result was not confirmed in a placebo-controlled phase III study (Goetz et al, , 2008.…”

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…Moreover, JL-18 impaired L-DOPA antiparkinsonian action at high dose, an effect that might well have been mediated by an interaction with D 2 receptors. More recently, the potent and selective D 4 antagonist L-745,870 significantly reduced LID severity, while increasing duration of on-time without disabling dyskinesia, in the MPTP-lesioned macaque (Huot et al, 2012a). That last study determined pharmacokinetic parameters and brain levels of L-745,870 associated with an antidyskinetic effect and established that L-745,870 alleviated LID at brain levels at which it blocked .…”

The highly-selective 5-HT1A agonist F15599 reduces l-DOPA-induced dyskinesia without compromising anti-parkinsonian benefits in the MPTP-lesioned macaque

“…*: P < 0.05 when compared to vehicle/vehicle; **: P < 0.01 when compared to vehicle/vehicle; ***: P < 0.001 when compared to vehicle/vehicle . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 magnitude of the anti-dyskinetic effect we previously achieved with the a-adrenoceptor antagonist fipamezole (Johnston et al, 2010b), the metabotropic glutamate 5 (mGlu5) receptor antagonist MTEP (Johnston et al, 2010a), the dopamine D 4 receptor antagonist L-745,870 (Huot et al, 2012a) and the nicotinic receptor agonist TC-8831 (Johnston et al, 2013). It also compares to that achieved by other groups in the MPTP-lesioned macaque with 5-HT 1A agonists such as sarizotan (Bibbiani et al, 2001;Gregoire et al, 2009) andeltoprazine (Bezard et al, 2013).…”