title: The novel antidyskinetic drug sarizotan elicits different functional responses at human D2-like dopamine receptors.
abstract: Sarizotan (EMD 128130) is a chromane derivative that exhibits affinity at serotonin and dopamine receptors. Sarizotan effectively suppresses levodopa-induced dyskinesia in primate and rodent models of Parkinson's disease, and tardive dyskinesia in a rodent model. Results from clinical trials suggest that sarizotan significantly alleviates levodopa-induced dyskinesia. The functional effects of sarizotan on individual dopamine receptor subtypes are not known. Here we report the functional effects of sarizotan on human D2-like dopamine receptors (D2S, D2L, D3, D4.2 and D4.4) individually expressed in the AtT-20 neuroendocrine cell line. Using the coupling of D2-like dopamine receptors to G-protein coupled inward rectifier potassium channels we determined that sarizotan is a full agonist at D3 and D4.4 receptors (EC50=5.6 and 5.4 nM, respectively) but a partial agonist at D2S, D2L and D4.2 receptors (EC50=29, 23 and 4.5 nM, respectively). Consistent with its partial agonist property, sarizotan is an antagonist at D2S and D2L receptors (IC50=52 and 121 nM, respectively). Using the coupling of D2-like dopamine receptors to adenylyl cyclase we determined that sarizotan is a full agonist at D2L, D3, D4.2 and D4.4 receptors (EC50=0.51, 0.47, 0.48 and 0.23 nM, respectively) but a partial agonist at D2S receptors (EC50=0.6 nM).
authors.affiliation: Department of Pharmacology and Physiology, UMDNJ-New Jersey Medical School, MSB, I-647, 185 South Orange Avenue, Newark, NJ 07103, USA. kuzhikev@umdnj.edu
authors.forename: Eldo V
authors.initials: EV
authors.lastname: Kuzhikandathil
authors.forename: Gerd D
authors.initials: GD
authors.lastname: Bartoszyk
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D018491:Dopamine Agonists / Q000493:pharmacokinetics; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000502:physiology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D009930:Organic Chemicals / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects*; D011188:Potassium / Q000494:pharmacology; D019257:Quinpirole / Q000493:pharmacokinetics; D011869:Radioligand Assay / Q000379:methods; D017448:Receptors, Dopamine D2 / Q000145:classification / Q000502:physiology*; D014162:Transfection / Q000379:methods; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D009930:Organic Chemicals; D017448:Receptors, Dopamine D2; D014316:Tritium; D019257:Quinpirole; C443959:sarizotan; D000242:Cyclic AMP; D011188:Potassium