title: 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.
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.
authors.affiliation: Juvantia Pharma Ltd., PharmaCity, Turku, Finland.
authors.forename: Juha-Matti
authors.initials: JM
authors.lastname: Savola
authors.forename: Michael
authors.initials: M
authors.lastname: Hill
authors.forename: Mia
authors.initials: M
authors.lastname: Engstrom
authors.forename: Hannele
authors.initials: H
authors.lastname: Merivuori
authors.forename: Siegfried
authors.initials: S
authors.lastname: Wurster
authors.forename: Steven G
authors.initials: SG
authors.lastname: McGuire
authors.forename: Susan H
authors.initials: SH
authors.lastname: Fox
authors.forename: Alan R
authors.initials: AR
authors.lastname: Crossman
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Brotchie
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001667:Binding, Competitive / Q000187:drug effects; D002144:Callithrix; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology; D005260:Female; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D007189:Indans / Q000494:pharmacology* / Q000627:therapeutic use; D007980:Levodopa / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D011869:Radioligand Assay; D051381:Rats; D018091:Receptors, AMPA / Q000187:drug effects; D011941:Receptors, Adrenergic / Q000187:drug effects; D011954:Receptors, Dopamine / Q000187:drug effects; D018079:Receptors, GABA / Q000187:drug effects; D011968:Receptors, Histamine / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000978:Antiparkinson Agents; D007093:Imidazoles; D007189:Indans; D018091:Receptors, AMPA; D011941:Receptors, Adrenergic; D011954:Receptors, Dopamine; D018079:Receptors, GABA; D011968:Receptors, Histamine; D016194:Receptors, N-Methyl-D-Aspartate; D011985:Receptors, Serotonin; D007980:Levodopa; C480818:fipamezole