title: Pharmacological profile of 2-bromoterguride at human dopamine D2, porcine serotonin 5-hydroxytryptamine 2A, and α2C-adrenergic receptors, and its antipsychotic-like effects in rats.
abstract: 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-hydroxytryptamine 2A (5-HT2A), α2C-adrenergic, and histamine H1 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-[(35)S]thio)triphosphate ([(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 with 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. 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.
authors.affiliation: Institute of Pharmacy, Free University of Berlin, Berlin, Germany (F.J., H.H.P.); Institute of Pharmacology and Toxicology, School of Veterinary Medicine, Free University of Berlin, Berlin, Germany (J.B., R.T.F., H.F.); and Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Erlangen, Germany (D.M., H.H., P.G.).
authors.forename: F
authors.initials: F
authors.lastname: Jantschak
authors.forename: J
authors.initials: J
authors.lastname: Brosda
authors.forename: R T
authors.initials: RT
authors.lastname: Franke
authors.forename: H
authors.initials: H
authors.lastname: Fink
authors.forename: D
authors.initials: D
authors.lastname: Möller
authors.forename: H
authors.initials: H
authors.lastname: Hübner
authors.forename: P
authors.initials: P
authors.lastname: Gmeiner
authors.forename: H H
authors.initials: HH
authors.lastname: Pertz
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000378:metabolism*; D016466:CHO Cells; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D018491:Dopamine Agonists / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008090:Lisuride / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D013552:Swine
chemical_list: D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D017448:Receptors, Dopamine D2; C006208:dironyl; D008090:Lisuride