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


OBJECTIVE
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.
Paquette
Melanie A
MA
Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR 97239, USA. paquette@ohsu.edu
Foley
Katherine
K
Brudney
Elizabeth G
EG
Meshul
Charles K
CK
Johnson
Steven W
SW
Berger
S Paul
SP
D000818:Animals; D002065:Buspirone / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000627:therapeutic use / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology; D007980:Levodopa / Q000627:therapeutic use / Q000633:toxicity*; D008297:Male; D010300:Parkinson Disease / Q000188:drug therapy; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000037:antagonists & inhibitors; D058825:Serotonin 5-HT1 Receptor Agonists; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D000097605:Sigma-1 Receptor
D002065:Buspirone; D015259:Dopamine Agents; D007980:Levodopa; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D017480:Receptors, sigma; D058825:Serotonin 5-HT1 Receptor Agonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D000097605:Sigma-1 Receptor; C050408:alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide