TY - JOUR
T1 - An in vivo pharmacological evaluation of pardoprunox (SLV308) - A novel combined dopamine D-2/D-3 receptor partial agonist and 5-HT1A receptor agonist with efficacy in experimental models of Parkinson's disease
AU - Jones, C. A.
AU - Johnston, L. C.
AU - Jackson, M. J.
AU - Smith, L. A.
AU - van Scharrenburg, G.
AU - Rose, S.
AU - Jenner, P. G.
AU - McCreary, A. C.
PY - 2010/8
Y1 - 2010/8
N2 - Partial D-2/3 dopamine (DA) receptor agonists provide a novel approach to the treatment of the motor symptoms of Parkinson's disease (PD) that may avoid common dopaminergic side-effects, including dyskinesia and psychosis. The present study focussed on the in vivo pharmacological and therapeutic characterisation of the novel D-2/3 receptor partial agonist and full 5-HT1A receptor agonist pardoprunox (SLV308; 7- [4-methyl-1-piperazinyl]-2(3H)-benzoxazolone monochloride). Pardoprunox induced contralateral turning behaviour in rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra pars compacta (SNpc) (MED = 0.03 mg/kg; po). In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets, pardoprunox dose-dependently increased locomotor activity (MED = 0.03 mg/kg; po) and decreased motor disability (MED = 0.03 mg/kg; po). The effects of pardoprunox were reversed by the D-2 antagonist sulpiride. In contrast pardoprunox attenuated novelty-induced locomotor activity (MED = 0.01 mg/kg; po), (+)-amphetamine-induced hyperlocomotion (MED = 0.3 mg/kg; po) and apomorphine-induced climbing (MED = 0.6 mg/kg; po) in rodents. Pardoprunox also induced 5-HT1A receptor-mediated behaviours, including flat body posture and tower lip retraction (MED = 0.3 mg/kg; pa) and these were reversed by the 5-HT1A receptor antagonist WAY100635. Collectively, these findings demonstrate that pardoprunox possesses
AB - Partial D-2/3 dopamine (DA) receptor agonists provide a novel approach to the treatment of the motor symptoms of Parkinson's disease (PD) that may avoid common dopaminergic side-effects, including dyskinesia and psychosis. The present study focussed on the in vivo pharmacological and therapeutic characterisation of the novel D-2/3 receptor partial agonist and full 5-HT1A receptor agonist pardoprunox (SLV308; 7- [4-methyl-1-piperazinyl]-2(3H)-benzoxazolone monochloride). Pardoprunox induced contralateral turning behaviour in rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra pars compacta (SNpc) (MED = 0.03 mg/kg; po). In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets, pardoprunox dose-dependently increased locomotor activity (MED = 0.03 mg/kg; po) and decreased motor disability (MED = 0.03 mg/kg; po). The effects of pardoprunox were reversed by the D-2 antagonist sulpiride. In contrast pardoprunox attenuated novelty-induced locomotor activity (MED = 0.01 mg/kg; po), (+)-amphetamine-induced hyperlocomotion (MED = 0.3 mg/kg; po) and apomorphine-induced climbing (MED = 0.6 mg/kg; po) in rodents. Pardoprunox also induced 5-HT1A receptor-mediated behaviours, including flat body posture and tower lip retraction (MED = 0.3 mg/kg; pa) and these were reversed by the 5-HT1A receptor antagonist WAY100635. Collectively, these findings demonstrate that pardoprunox possesses
U2 - 10.1016/j.euroneuro.2010.03.001
DO - 10.1016/j.euroneuro.2010.03.001
M3 - Article
SN - 1873-7862
VL - 20
SP - 582
EP - 593
JO - European Neuropsychopharmacology
JF - European Neuropsychopharmacology
IS - 8
ER -
