title: Atypical kinetics for a series of putative dopamine antagonists to reverse the low-magnitude Ca2+ phase in the dopamine-bound D2short receptor state.
abstract: Real-time analysis of dopamine:antagonist interactions at the recombinant D2short receptor was performed by measuring time-dependent Ca2+ responses following activation of a chimeric Galphaq/o protein in CHO-K1 cells. Terguride (57%), +-UH 232 (20%) and buspirone (16%) demonstrated dopamine-like intrinsic activity at the presumably unoccupied, dopamine-free receptor; remoxipride, pipamperone and L 741626 being silent at 1 microM. Each of the putative antagonists (1 microM) displayed a transient reversal capacity of the low-magnitude Ca2+ phase in the dopamine-bound receptor state ( E(rev): 68%-92% vs. 1 microM tropapride) with a t1/2 between 8.8 s and 13.9 s upon antagonist addition; this capacity was either almost fully [remoxipride, pipamperone and +-UH 232] or partially [buspirone (31%), terguride (45%) and L 741626 (70%)] lost upon further incubation. The biphasic reversal Ca2+ profile of these dopamine antagonists is different from previously characterised dopamine antagonists which display either full reversal of the low-magnitude Ca2+ response with a fast or slow onset of action, or partial reversal stably present over the entire incubation period. The dynamic Ca2+ data strongly suggest that the dopamine D2short receptor can be blocked via multiple molecular mechanisms.
authors.affiliation: Department of Cellular and Molecular Biology, Centre de Recherche Pierre Fabre, 17, avenue Jean Moulin, 81106 Castres Cédex, France. peter.pauwels@pierre-fabre.com
authors.forename: Petrus J
authors.initials: PJ
authors.lastname: Pauwels
authors.forename: Wouter
authors.initials: W
authors.lastname: Koek
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism*; D006224:Cricetinae; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D011994:Recombinant Proteins; D002118:Calcium; D004298:Dopamine