Objective: To investigate the effect of the highly-selective serotonin 2A (5-HT2A) receptor EMD-281,014 on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced psychosis-like behaviours (PLBs) and dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset model of Parkinson’s disease (PD).

Background: Psychosis and dyskinesia undermine the quality of life of as many as 50-95% of patients with advanced PD. Available therapies are few, and they may elicit important side effects. Whereas there is mounting evidence indicating that antagonising 5-HT2A receptors is effective at alleviating both psychosis and dyskinesia, the drugs used so far, both pre-clinically and clinically, were not entirely selective for this target. Here, we have used the potent and highly-selective 5-HT2A antagonist EMD-281,014, which harbours  2,000-fold selectivity over its next target, and have assessed its effect on dyskinesia, PLBs and parkinsonism in the MPTP-lesioned primate.

Methods: Six marmosets were rendered parkinsonian by MPTP administration. Following repeated administration of L-DOPA to elicit stable PLBs and dyskinesia, they were administered acute challenges of EMD-281,014 (0.01, 0.03, 0.1 mg/kg) or vehicle, in combinaison with L-DOPA after which the severity of PLBs, dyskinesia and parkinsonian disability was rated.

Results: EMD-281,014 (0.03 and 0.1 mg/kg) significantly reduced the severity of peak dose PLBs, by ≈ 42.5% and ≈ 45.9% (P < 0.05 and P < 0.001), respectively when compared to L-DOPA/vehicle. Peak dose dyskinesia was also reduced, by ≈ 41.8% and ≈ 54.5% (P < 0.05 and P < 0.001), respectively, when EMD-281,014 (0.03 and 0.1 mg/kg) was added to L-DOPA, compared to L-DOPA/vehicle. The anti-psychotic and anti-dyskinetic effects of EMD-281,014 were achieved without interfering with L-DOPA anti-parkinsonian action.

Conclusions: Our results suggest that highly-selective blockade of 5-HT2A receptors is effective at alleviating psychosis and dyskinesia in PD, without interfering with L-DOPA anti-parkinsonian action. EMD-281,014 has already been tested in clinical settings and could therefore be advanced rapidly to Phase II trials in PD patients experiencing dyskinesia and psychotic features.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/highly-selective-blockade-of-5-ht2a-receptors-with-emd-281014-reduces-the-severity-of-l-dopa-induced-psychosis-and-dyskinesia-in-the-mptp-lesioned-marmoset-model-of-parkinsons-disease/