RT Journal Article
SR Electronic
T1 Constitutive Coupling of a Chimeric Dopamine D<sub>2</sub>/α<sub>1</sub>
<sub>B</sub> Receptor to the Phospholipase C Pathway: Inverse Agonism to Silent Antagonism by Neuroleptic Drugs
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 380
OP 390
DO 10.1124/jpet.102.040535
VO 304
IS 1
A1 Thierry Wurch
A1 Elisa A. Boutet-Robinet
A1 Christiane Palmier
A1 Francis C. Colpaert
A1 Petrus J. Pauwels
YR 2003
UL http://jpet.aspetjournals.org/content/304/1/380.abstract
AB Neuroleptic drugs have been suggested to act as inverse agonists at the dopamine D2 receptor, but no link between therapeutic efficacy and ligand's intrinsic activity could be determined. Since the resolving capacity to monitor inverse agonism at dopamine D2 receptors is limited, we speculated that receptor constitutive activation could be enhanced by constructing chimeric D2/α1B receptors. Marked inverse agonist responses with a series of dopamine antagonists were obtained by: 1) exchange of the D2short receptor's 3ICL by that of the α1B-adrenoceptor, 2) incorporation of an activating mutation (Ala279Glu) in the distal portion of its 3ICL, and 3) coexpression with a Gα11 protein. This chimeric D2/α1B receptor construct displayed a ligand binding profile comparable to that of the wild-type (wt) D2short receptor and an effector activation profile close to that of the wt α1B-adrenoceptor. Most of the dopamine antagonists attenuated by −54 to −59% basal inositol phosphates (IP) formation, thus clearly acting as inverse agonists. Ziprasidone behaved as a silent antagonist (+5% versus basal IP level) and antagonized both dopamine-mediated (pKB, 7.61) and tropapride-mediated (pKB, 8.52) IP responses. Clozapine, olanzapine, and raclopride displayed partial inverse agonist properties (−31, −67, and −71% versus tropapride, respectively), whereas bromerguride (+63%) andcis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino tetralin) [(+)-UH 232] (+88%) demonstrated positive agonism. In conclusion, analyses with the chimeric D2/α1B Ala279Glu 3ICL receptor construct suggest that neuroleptic drugs can be differentiated on the basis of their intrinsic activity, as they can either activate, inhibit, or be silent at this receptor construct. The American Society for Pharmacology and Experimental Therapeutics