An in vivo pharmacological evaluation of pardoprunox (SLV308) — A novel combined dopamine D2/D3 receptor partial agonist and 5-HT1A receptor agonist with efficacy in experimental models of Parkinson's disease

Jones, C.A.; Johnston, L.C.; Jackson, M.J.; Smith, L.A.; van Scharrenburg, G.; Rose, S.; Jenner, P.G.; McCreary, A.C.

doi:10.1016/j.euroneuro.2010.03.001

« Previous Next »European Neuropsychopharmacology
Volume 20, Issue 8 , Pages 582-593, August 2010

An in vivo pharmacological evaluation of pardoprunox (SLV308) — A novel combined dopamine D₂/D₃ receptor partial agonist and 5-HT_1A receptor agonist with efficacy in experimental models of Parkinson's disease

C.A. Jones
- Abbott Pharmaceuticals B.V., Weesp, The Netherlands (formerly Solvay Pharmaceuticals B.V.)
- These authors contributed equally.
- Present address: School of Biomedical Sciences, Queen's Medical Centre, University of Nottingham, NG7 2UH, UK.
L.C. Johnston
- Neurodegenerative Diseases Research Centre, School of Biomedical and Health Sciences, King's College London, London SE1 1UL, UK
- These authors contributed equally.
- Present address: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
M.J. Jackson
- Neurodegenerative Diseases Research Centre, School of Biomedical and Health Sciences, King's College London, London SE1 1UL, UK
L.A. Smith
- Neurodegenerative Diseases Research Centre, School of Biomedical and Health Sciences, King's College London, London SE1 1UL, UK
G. van Scharrenburg
- Abbott Pharmaceuticals B.V., Weesp, The Netherlands (formerly Solvay Pharmaceuticals B.V.)
S. Rose
- Neurodegenerative Diseases Research Centre, School of Biomedical and Health Sciences, King's College London, London SE1 1UL, UK
P.G. Jenner
- Neurodegenerative Diseases Research Centre, School of Biomedical and Health Sciences, King's College London, London SE1 1UL, UK
A.C. McCreary
- Abbott Pharmaceuticals B.V., Weesp, The Netherlands (formerly Solvay Pharmaceuticals B.V.)
- Corresponding author. Tel.: +31 294 479 514; fax: +31 294 410 069.

Received 28 September 2009; received in revised form 5 February 2010; accepted 10 March 2010. published online 03 May 2010.

Abstract

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-HT_1A 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=0.03mg/kg; po). In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets, pardoprunox dose-dependently increased locomotor activity (MED=0.03mg/kg; po) and decreased motor disability (MED=0.03mg/kg; po). The effects of pardoprunox were reversed by the D₂ antagonist sulpiride. In contrast pardoprunox attenuated novelty-induced locomotor activity (MED=0.01mg/kg; po), (+)-amphetamine-induced hyperlocomotion (MED=0.3mg/kg; po) and apomorphine-induced climbing (MED=0.6mg/kg; po) in rodents. Pardoprunox also induced 5-HT_1A receptor-mediated behaviours, including flat body posture and lower lip retraction (MED=0.3mg/kg; po) and these were reversed by the 5-HT_1A receptor antagonist WAY100635. Collectively, these findings demonstrate that pardoprunox possesses dopamine D2/3 partial agonist effects, 5-HT1A agonist effects and reduces parkinsonism in animal models. functional DA D₂ receptor partial agonist activity and is effective in experimental models predictive of efficacy in PD. The presence of functional 5-HT_1A agonist activity might confer anti-dyskinetic activity and have effects that control neuropsychiatric components of PD.