The classic manifestations of Parkinson's disease (PD) are caused by the degeneration of dopaminergic neurons of the substantia nigra; long-term treatment of Parkinson's disease with l-DOPA is marred by the development of abnormal involuntary movements, dyskinesia, which negatively affects quality of life. Huot et al. investigated the potential antidyskinetic effect of selective dopamine D4 antagonism by 3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H-pyrrolo[2,3-b]pyridine (l-745,870), a compound with an excellent safety and tolerability record in phase I/II clinical studies, for non-PD indications. This study demonstrated that oral administration of L-745,870 in combination with l-DOPA significantly alleviates dyskinesia. The magnitude of the antidyskinetic effect achieved compares advantageously with the magnitude of the antidyskinetic effect previously achieved with famotidine and fipamezole. This reduction in dyskinesia severity was accompanied by a reduction in bad quality ON-time and an extension in good quality ON-time duration. It is noteworthy that the antidyskinetic efficacy of L-745,870 was achieved without compromising l-DOPA antiparkinsonian benefit and at brain levels at which L-745,870 is selective for D4 receptors, thereby identifying D4 receptors as a promising target for dyskinesia. Moreover, effective plasma levels of L-745,870 obtained in this study are in the range of those that were demonstrated to be well-tolerated in human trials.
See article at J Pharmacol Exp Ther 2012, 342:576–585.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics