Pharmacological profile of 2-bromoterguride at human dopamine D 2, porcine serotonin 5-hydroxytryptamine 2A, and α 2C-adrenergic receptors, and its antipsychotic-like effects in rats
Jantschak F, Brosda J, Franke RT, Fink H, Möller D, Hübner H, Gmeiner P, Pertz HH (2013)
Publication Language: English
Publication Type: Journal article, Original article
Publication year: 2013
Journal
Original Authors: Jantschak F., Brosda J., Franke R.T., Fink H., Moller D., Hubner H., Gmeiner P., Pertz H.H.
Publisher: American Society for Pharmacology and Experimental Therapeutics (ASPET)
Book Volume: 347
Pages Range: 57-68
Journal Issue: 1
Abstract
Dopaminergic, serotonergic, and adrenergic receptors are targets for therapeutic actions in schizophrenia. Dopamine D receptor partial agonists such as aripiprazole represent a treatment option for patients with this severe disorder. The ineffectiveness of terguride, another D receptor partial agonist, in treating schizophrenia was recently attributed to its considerably high intrinsic activity at D receptors. In this study, we used functional assays for recombinant D receptors and native 5-hydroxytryptamine 2A (5-HT), α- adrenergic, and histamine H receptors to compare the pharmacological properties of terguride and three of its halogenated derivatives (2-chloro-, 2-bromo-, 2-iodoterguride) with those of aripiprazole. Subsequently, we studied the antidopaminergic effects of 2-bromoterguride using amphetamine-induced locomotion (AIL). Its influence on spontaneous behavior was tested in the open field. Extrapyramidal side effect (EPS) liability was evaluated by catalepsy test. In a guanosine 5′-O-(3-[S]thio)triphosphate ([ S]GTPγS) binding assay, 2-chloro-, 2-bromo-, and 2-iodoterguride produced intrinsic activities at human D (hD) receptors that were half as high as the intrinsic activity for terguride; aripiprazole lacked agonist activity. 2-Bromoterguride and aripiprazole activated D receptor-mediated inhibition of cAMP accumulation to the same extent; intrinsic activity was half as high as that of terguride. All compounds tested behaved as antagonists at human D /Gα (hD/Gα) receptors. Compared with aripiprazole, terguride and its derivatives displayed higher affinity at porcine 5-HT receptors and α- adrenoceptors and lower affinity at H receptors. 2-Bromoterguride inhibited AIL and did not induce catalepsy in rats. Because of its in vitro and in vivo properties, 2-bromoterguride may be a strong candidate for the treatment of schizophrenia with a lower risk to induce EPS. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.
Authors with CRIS profile
Dorothée Weikert
Lehrstuhl für Pharmazeutische Chemie
Harald Hübner
Lehrstuhl für Pharmazeutische Chemie
Peter Gmeiner
Lehrstuhl für Pharmazeutische Chemie
Additional Organisation(s)
Involved external institutions
Germany (DE)How to cite
APA:
Jantschak, F., Brosda, J., Franke, R.T., Fink, H., Möller, D., Hübner, H.,... Pertz, H.H. (2013). Pharmacological profile of 2-bromoterguride at human dopamine D 2, porcine serotonin 5-hydroxytryptamine 2A, and α 2C-adrenergic receptors, and its antipsychotic-like effects in rats. Journal of Pharmacology and Experimental Therapeutics, 347(1), 57-68. https://dx.doi.org/10.1124/jpet.113.205997
MLA:
Jantschak, Florian, et al. "Pharmacological profile of 2-bromoterguride at human dopamine D 2, porcine serotonin 5-hydroxytryptamine 2A, and α 2C-adrenergic receptors, and its antipsychotic-like effects in rats." Journal of Pharmacology and Experimental Therapeutics 347.1 (2013): 57-68.
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