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

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 = 0.03 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-HT 1A receptor-mediated behaviours, including flat body posture and lower lip retraction (MED = 0.3 mg/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 D 2 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.