title: Cariprazine (RGH-188), a potent D3/D2 dopamine receptor partial agonist, binds to dopamine D3 receptors in vivo and shows antipsychotic-like and procognitive effects in rodents.
abstract: We investigated the in vivo effects of orally administered cariprazine (RGH-188; trans-N-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-N',N'-dimethyl-urea), a D(3)/D(2) dopamine receptor partial agonist with ∼10-fold preference for the D(3) receptor. Oral bioavailability of cariprazine at a dose of 1mg/kg in rats was 52% with peak plasma concentrations of 91ng/mL. Cariprazine 10mg/kg had good blood-brain barrier penetration, with a brain/plasma AUC ratio of 7.6:1. In rats, cariprazine showed dose-dependent in vivo displacement of [(3)H](+)-PHNO, a dopamine D(3) receptor-preferring radiotracer, in the D(3) receptor-rich region of cerebellar lobules 9 and 10. Its potent inhibition of apomorphine-induced climbing in mice (ED(50)=0.27mg/kg) was sustained for 8h. Cariprazine blocked amphetamine-induced hyperactivity (ED(50)=0.12mg/kg) and conditioned avoidance response (CAR) (ED(50)=0.84mg/kg) in rats, and inhibited the locomotor-stimulating effects of the noncompetitive NMDA antagonists MK-801 (ED(50)=0.049mg/kg) and phencyclidine (ED(50)=0.09mg/kg) in mice and rats, respectively. It reduced novelty-induced motor activity of mice (ED(50)=0.11mg/kg) and rats (ED(50)=0.18mg/kg) with a maximal effect of 70% in both species. Cariprazine produced no catalepsy in rats at up to 100-fold dose of its CAR inhibitory ED(50) value. Cariprazine 0.02-0.08mg/kg significantly improved the learning performance of scopolamine-treated rats in a water-labyrinth learning paradigm. Though risperidone, olanzapine, and aripiprazole showed antipsychotic-like activity in many of these assays, they were less active against phencyclidine and more cataleptogenic than cariprazine, and had no significant effect in the learning task. The distinct in vivo profile of cariprazine may be due to its higher affinity and in vivo binding to D(3) receptors versus currently marketed typical and atypical antipsychotics.
authors.affiliation: Pharmacology and Drug Safety Research, Gedeon Richter Plc, Gyömrői u. 19-21, 1103 Budapest, Hungary. i.gyertyan@richter.hu
authors.forename: István
authors.initials: I
authors.lastname: Gyertyán
authors.forename: Béla
authors.initials: B
authors.lastname: Kiss
authors.forename: Katalin
authors.initials: K
authors.lastname: Sághy
authors.forename: Judit
authors.initials: J
authors.lastname: Laszy
authors.forename: Györgyi
authors.initials: G
authors.lastname: Szabó
authors.forename: Tamás
authors.initials: T
authors.lastname: Szabados
authors.forename: Larisza I
authors.initials: LI
authors.lastname: Gémesi
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pásztor
authors.forename: Mária
authors.initials: M
authors.lastname: Zájer-Balázs
authors.forename: Margit
authors.initials: M
authors.lastname: Kapás
authors.forename: Eva Ágai
authors.initials: EÁ
authors.lastname: Csongor
authors.forename: György
authors.initials: G
authors.lastname: Domány
authors.forename: Károly
authors.initials: K
authors.lastname: Tihanyi
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Szombathelyi
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018697:Nootropic Agents / Q000494:pharmacology*; D010879:Piperazines / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000378:metabolism* / Q000502:physiology
chemical_list: D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D018697:Nootropic Agents; D010879:Piperazines; D050637:Receptors, Dopamine D3; C533287:cariprazine