The effects of BMY-14802 against L-DOPA- and dopamine agonist-induced dyskinesia in the hemiparkinsonian rat.

Abstract

RATIONALE:

L-DOPA continues to be the primary treatment for patients with Parkinson's disease; however, the benefits of long-term treatment are often accompanied by debilitating side effects known as dyskinesias. In recent years, several 5-HT1A receptor agonists have been found to reduce dyskinesia in clinical and experimental models of PD. The purported sigma-1 antagonist, BMY-14802 has been previously demonstrated to reduce L-DOPA induced dyskinesia in a 5-HT1A receptor dependent manner.

OBJECTIVE:

In the present study, we extend these findings by examining the anti-dyskinetic potential of BMY-14802 against L-DOPA, the D1 receptor agonist SKF81297 and the D2 receptor agonist, quinpirole, in the hemi-parkinsonian rat model. In addition, the receptor specificity of BMY-14802's effects was evaluated using WAY-100635, a 5-HT1A receptor antagonist.

RESULTS:

Results confirmed the dose-dependent (20 > 10 > 5 mg/kg) anti-dyskinetic effects of BMY-14802 against L-DOPA with preservation of anti-parkinsonian efficacy at 10 mg/kg. BMY-14802 at 10 and 20 mg/kg also reduced dyskinesia induced by both D1 and D2 receptor agonists. Additionally, BMY-14802's anti-dyskinetic effects against L-DOPA, but not SKF81297 or quinpirole, were reversed by WAY-100635 (0.5 mg/kg).

CONCLUSION:

Collectively, these findings demonstrate that BMY-14802 provides anti-dyskinetic relief against L-DOPA and direct DA agonist in a preclinical model of PD, acting via multiple receptor systems and supports the utility of such compounds for the improved treatment of PD.

• Authors: Nirmal Bhide, David Lindenbach, Margaret A Surrena, Adam A Goldenberg, Christopher Bishop, S Paul Berger, Melanie A Paquette
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 227 Issue 3 Pg. 533-44 (Jun 2013) ISSN: 1432-2072 [Electronic] Germany
• PMID: 23389756 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antiparkinson Agents
• Dopamine Agonists
• Pyrimidines
• Receptors, Dopamine D1
• alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol
• Receptor, Serotonin, 5-HT1A
• Levodopa

Topics

• Animals
• Antiparkinson Agents (administration & dosage, adverse effects, therapeutic use)
• Disease Models, Animal
• Dopamine Agonists (administration & dosage, adverse effects, therapeutic use)
• Dyskinesia, Drug-Induced (drug therapy, etiology)
• Levodopa (administration & dosage, adverse effects, therapeutic use)
• Male
• Motor Activity (drug effects)
• Parkinson Disease (drug therapy)
• Pyrimidines (administration & dosage, pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptor, Serotonin, 5-HT1A (metabolism)
• Receptors, Dopamine D1 (metabolism)