The sigma-1 antagonist BMY-14802 inhibits L-DOPA-induced abnormal involuntary movements by a WAY-100635-sensitive mechanism.

Abstract

RATIONALE:

Levodopa (L-DOPA), the gold standard treatment for Parkinson's disease (PD), eventually causes L-DOPA-induced dyskinesia (LID) in up to 80% of patients. In the 6-hydroxydopamine (6-OHDA) rat model of PD, L-DOPA induces a similar phenomenon, which has been termed abnormal involuntary movement (AIM). We previously demonstrated that BMY-14802 suppresses AIM expression in this model.

OBJECTIVES:

Although BMY-14802 is widely used as a sigma-1 antagonist, it is also an agonist at serotonin (5-HT) 1A and adrenergic alpha-1 receptors. The current study was conducted to determine which of these mechanisms underlies BMY-14802's AIM-suppressing effect. This characterization included testing the 5-HT1A agonist buspirone and multiple sigma agents. When these studies implicated a 5-HT1A mechanism, we subsequently undertook a pharmacological reversal study, evaluating whether the 5-HT1A antagonist WAY-100635 counteracted BMY-14802's AIM-suppressing effects.

RESULTS:

Buspirone dose-dependently suppressed AIM, supporting past findings. However, no AIM-suppressing effects were produced by drugs with effects at sigma receptors, including BD-1047, finasteride, SM-21, DTG, trans-dehydroandrosterone (DHEA), carbetapentane, and opipramol. Finally, we show for the first time that the AIM-suppressing effect of BMY-14802 was dose-dependently prevented by WAY-100635 but not by the alpha-1 antagonist prazosin.

CONCLUSIONS:

BMY-14802 exerts its AIM-suppressing effects via a 5-HT1A agonist mechanism, similar to buspirone. Other 5-HT1A agonists have failed clinical trials, possibly due to submicromolar affinity at other receptors, including D2, which may exacerbate PD symptoms. BMY-14802 is a promising candidate for clinical trials due to its extremely low affinity for the D2 receptor and lack of extrapyramidal effects during prior clinical trials for schizophrenia.

• Authors: Melanie A Paquette, Katherine Foley, Elizabeth G Brudney, Charles K Meshul, Steven W Johnson, S Paul Berger
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 204 Issue 4 Pg. 743-54 (Jul 2009) ISSN: 1432-2072 [Electronic] Germany
• PMID: 19283364 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Dopamine Agents
• Piperazines
• Pyridines
• Pyrimidines
• Receptors, sigma
• Serotonin 5-HT1 Receptor Agonists
• Serotonin Antagonists
• Serotonin Receptor Agonists
• sigma-1 receptor
• alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol
• Levodopa
• N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
• Buspirone

Topics

• Animals
• Buspirone (administration & dosage, pharmacology)
• Disease Models, Animal
• Dopamine Agents (therapeutic use, toxicity)
• Dose-Response Relationship, Drug
• Dyskinesia, Drug-Induced (drug therapy, etiology)
• Levodopa (therapeutic use, toxicity)
• Male
• Parkinson Disease (drug therapy)
• Piperazines (administration & dosage, pharmacology)
• Pyridines (administration & dosage, pharmacology)
• Pyrimidines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, sigma (antagonists & inhibitors)
• Serotonin 5-HT1 Receptor Agonists
• Serotonin Antagonists (administration & dosage, pharmacology)
• Serotonin Receptor Agonists (pharmacology)