The highly selective 5-HT2A antagonist EMD-281,014 reduces dyskinesia and psychosis in the l-DOPA-treated parkinsonian marmoset.

Abstract

Blockade of serotonin 2A (5-HT2A) receptors is regarded as an anti-dyskinetic and anti-psychotic strategy in Parkinson's disease (PD). However, the 5-HT2A antagonists tested so far exhibited affinity for other receptors, which might have played a role in their action. EMD-281,014 is the most selective 5-HT2A antagonist available, with approximately 2,000-fold selectivity over serotonin 2C (5-HT2C) receptors. EMD-281,014 was previously tested in the clinic and has high translational potential. In the present study, we assessed the effect of EMD-281,014 on dyskinesia and psychosis in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset. We first determined the pharmacokinetic profile of EMD-281,014 in the marmoset, after which doses leading to clinically-relevant plasma levels (0.01, 0.03 and 0.1 mg/kg) or vehicle were administered to MPTP-lesioned marmosets, in combination with L-3,4-dihydroxyphenylalanine (l-DOPA). The effects of EMD-281,014 on dyskinesia, psychosis-like behaviours (PLBs) and parkinsonism were then evaluated. When added to l-DOPA, EMD-281,014 (0.03 and 0.1 mg/kg) reduced peak dose dyskinesia, by 41.8% and 54.5% (P < 0.05 and P < 0.001), when compared to l-DOPA/vehicle. EMD-281,014 (0.03 and 0.1 mg/kg) also significantly reduced the severity of peak dose PLBs, by 42.5% and 45.9% (P < 0.05 and P < 0.001), when compared to vehicle. The anti-dyskinetic and anti-psychotic effects of EMD-281,014 were achieved without interfering with l-DOPA anti-parkinsonian action. Our results suggest that highly-selective 5-HT2A receptor blockade with EMD-281,014 is an effective way to alleviate both dyskinesia and psychosis in PD, without adversely affecting parkinsonian disability.

• Authors: Adjia Hamadjida, Stephen G Nuara, Dominique Bédard, Fleur Gaudette, Francis Beaudry, Jim C Gourdon, Philippe Huot
• Journal: Neuropharmacology (Neuropharmacology) Vol. 139 Pg. 61-67 (09 01 2018) ISSN: 1873-7064 [Electronic] England
• PMID: 29969592 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Antiparkinson Agents
• EMD 281014
• Indoles
• Piperazines
• Serotonin 5-HT2 Receptor Antagonists
• Levodopa

Topics

• Animals
• Antiparkinson Agents (adverse effects)
• Callithrix
• Dose-Response Relationship, Drug
• Drug Interactions
• Dyskinesia, Drug-Induced (drug therapy, metabolism)
• Female
• Indoles (pharmacokinetics, pharmacology)
• Levodopa (adverse effects)
• MPTP Poisoning (drug therapy, metabolism)
• Male
• Motor Activity (drug effects)
• Piperazines (pharmacokinetics, pharmacology)
• Psychoses, Substance-Induced (drug therapy, metabolism)
• Serotonin 5-HT2 Receptor Antagonists (pharmacokinetics, pharmacology)