Fipamezole (JP-1730) is a potent alpha2 adrenergic receptor antagonist that reduces levodopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson's disease.

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Abstract

Previous studies in the MPTP-lesioned primate model of Parkinson's disease have demonstrated that alpha(2) adrenergic receptor antagonists such as idazoxan, rauwolscine, and yohimbine can alleviate L-dopa-induced dyskinesia and, in the case of idazoxan, enhance the duration of anti-parkinsonian action of L-dopa. Here we describe a novel alpha(2) antagonist, fipamezole (JP-1730), which has high affinity at human alpha(2A) (K(i), 9.2 nM), alpha(2B) (17 nM), and alpha(2C) (55 nM) receptors. In functional assays, the potent antagonist properties of JP-1730 were demonstrated by its ability to reduce adrenaline-induced (35)S-GTPgammaS binding with K(B) values of 8.4 nM, 16 nM, 4.7 nM at human alpha(2A), alpha(2B), and alpha(2C) receptors, respectively. Assessment of the ability of JP-1730 to bind to a range of 30 other binding sites showed that JP-1730 also had moderate affinity at histamine H1 and H3 receptors and the serotonin (5-HT) transporter (IC(50) 100 nM to 1 microM). In the MPTP-lesioned marmoset, JP-1730 (10 mg/kg) significantly reduced L-dopa-induced dyskinesia without compromising the anti-parkinsonian action of L-dopa. The duration of action of the combination of L-dopa and JP-1730 (10 mg/kg) was 66% greater than that of L-dopa alone. These data suggest that JP-1730 is a potent alpha(2) adrenergic receptor antagonist with potential as an anti-dyskinetic agent in the treatment of Parkinson's disease. Copyright 2003 Movement Disorder Society

Keyword(s)

Animals; Callithrix; Female; Male; Radioligand Assay; Rats; adverse effects: Antiparkinson Agents; adverse effects: Levodopa; antagonists & inhibitors: Receptors, Adrenergic, alpha-2; drug effects: Binding, Competitive; drug effects: Receptors, AMPA; drug effects: Receptors, Adrenergic; drug effects: Receptors, Dopamine; drug effects: Receptors, GABA; drug effects: Receptors, Histamine; drug effects: Receptors, N-Methyl-D-Aspartate; drug effects: Receptors, Serotonin; drug therapy: Dyskinesia, Drug-Induced; drug therapy: Parkinsonian Disorders; pharmacology: Adrenergic alpha-Antagonists; pharmacology: Imidazoles; pharmacology: Indans

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