Publikationsdatenbank

Pharmacological Profile of 2-Bromoterguride at Human Dopamine D2, Porcine Serotonin 5-HT2A and α2C-Adrenergic Receptors, and its Antipsychotic-Like Effects in Rats (2013)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Jantschak, Florian

Brosda, Jan (WE 14)

Franke, Robert T (WE 14)

Fink, Heidrun (WE 14)

Moller, Dorothee

Hubner, Harald

Gmeiner, Peter

Pertz, Heinz H

Quelle

The journal of pharmacology and experimental therapeutics

Bandzählung: 347

Heftzählung: 1

Seiten: 57 – 68

ISSN: 0022-3565

Sprache

Englisch

Verweise

Pubmed: 23863695

Kontakt

Institut für Pharmakologie und Toxikologie

Koserstr. 20
14195 Berlin
+49 30 838 53221
pharmakologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

Dopaminergic, serotonergic and adrenergic receptors are targets for therapeutic actions in schizophrenia. Dopamine D2 receptor partial agonists such as aripiprazole represent a treatment option for patients with this severe disorder. The ineffectiveness of terguride, another D2 receptor partial agonist, in treating schizophrenia was recently attributed to its considerably high intrinsic activity at D2 receptors. In this study, we used functional assays for recombinant D2 receptors and native 5-HT2A, α2C-adrenergic, and histamine H1 receptors to compare the pharmacological properties of terguride and three halogenated derivatives of it (2-chloro-, 2-bromo-, 2-iodoterguride) with those of aripiprazole. Subsequently, we studied the antidopaminergic effects of 2-bromoterguride using amphetamine-induced locomotion (AIL). Influence on spontaneous behavior was tested in the open field. Extrapyramidal side-effect (EPS) liability was evaluated by catalepsy test. In a [(35)S]GTPγS binding assay, 2-chloro-, 2-bromo-, and 2-iodoterguride produced intrinsic activities at human D2short (hD2S) receptors that were half as high as the intrinsic activity for terguride; aripiprazole lacked agonist activity. 2-Bromoterguride and aripiprazole activated D2S 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 D2long/Gαo (hD2L/Gαo) receptors. Compared to aripiprazole, terguride and its derivatives displayed higher affinity at porcine 5-HT2A receptors and α2C-adrenoceptors and lower affinity at H1 receptors. 2-Bromoterguride inhibited AIL and did not induce catalepsy in rats. Due to 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.