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

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

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

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-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
Original languageEnglish
Pages (from-to)582 - 593
Number of pages12
JournalEuropean Neuropsychopharmacology
Volume20
Issue number8
DOIs
Publication statusPublished - Aug 2010

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