Receptor pharmacology of the antidyskinetic drug sarizotan

Objective: Sarizotan is in clinical development for levodopa-associated dyskinesia in Parkinson patients. Sarizotan was investigated for its properties at human 5HT1A, D2, D3 and D4 receptors in functional in vitro assays and on the extracellular glutamate levels in the motor cortex and the ipsilateral dorsolateral striatum by dual-probe microdialysis in awake rats. Background: In receptor binding assays, sarizotan exhibited affinity to 5HT1A, D2, D3 and D4 receptors. Besides dopamine D1, D2 and D3 receptors in the basal ganglia, 5HT1A receptors in the cortex, modulating the corticostriatal glutamate pathways, affect striatal GABA output neurons in basal ganglia circuitry. Methods: Human 5HT1A or D2-like receptors were stably expressed in CHO cells for [35S]GTPS binding assay or in AtT-20 mouse pituitary cells for measuring drug-activated G-protein-coupled inward rectifier potassium currents (GIRK; patch clamp technique) or changes in cAMP levels (stimulated with 10 M forskolin). Microdialysis probes were implanted into the motor cortex and ipsilateral dorsolateral striatum. Sarizotan was administered systemically (0.1-10 mg/kg s.c.) or included in the cortical perfusion medium (10 M) for 60 min. WAY100135 (10 M) was intracortically perfused 20 min prior to the application of sarizotan. Perfusates were collected every 20 min for 2 hours. Results: The following table summarizes the effect of sarizotan in the functional assays: Receptor Binding IC50 GTPS GIRK cAMP 5HT1A 0.1 3.5* 6.2* 1.5* D2S 17 38** 20* 0.6* D3 7 128** 5.6* 0.5* D4.2 3 30** 4.5* 0.5* D4.4 4 0.9* 5.4* 0.2* [nM]; * EC50 (Agonist) and ** IC50 (Antagonist) Dual-probe microdialysis revealed that sarizotan (s.c. or perfused into the motor cortex) produced a significant (20%-30%) reduction of cortical and striatal glutamate levels. The inhibitory effects of s.c. sarizotan on cortical and striatal glutamate levels were counteracted by intracortical perfusion with the 5HT1A receptor antagonist WAY100135. Conclusion: Sarizotan is an agonist at 5HT1A receptors and most likely also at D3 and D4 receptors, and a partial agonist at D2 receptors in functional assays. Its antidyskinetic effect may involve at least a reduction of the activity of the corticostriatal glutamate pathways with diminished activation of striatal GABA output neurons in basal ganglia circuitry.