Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile.
Cariprazine {RGH-188; trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea hydrochloride}, a novel candidate antipsychotic, demonstrated approximately 10-fold higher affinity for human D(3) versus human D(2L) and human D(2S) receptors (pKi 10.07, 9.16, and 9.31, respectively). It displayed high affinity at human serotonin (5-HT) type 2B receptors (pK(i) 9.24) with pure antagonism. Cariprazine had lower affinity at human and rat hippocampal 5-HT(1A) receptors (pK(i) 8.59 and 8.34, respectively) and demonstrated low intrinsic efficacy. Cariprazine displayed low affinity at human 5-HT(2A) receptors (pK(i) 7.73). Moderate or low affinity for histamine H(1) and 5-HT(2C) receptors (pK(i) 7.63 and 6.87, respectively) suggest cariprazine's reduced propensity for adverse events related to these receptors. Cariprazine demonstrated different functional profiles at dopamine receptors depending on the assay system. It displayed D(2) and D(3) antagonism in [(35)S]GTPgammaS binding assays, but stimulated inositol phosphate (IP) production (pEC(50) 8.50, E(max) 30%) and antagonized (+/-)-quinpirole-induced IP accumulation (pK(b) 9.22) in murine cells expressing human D(2L) receptors. It had partial agonist activity (pEC(50) 8.58, E(max) 71%) by inhibiting cAMP accumulation in Chinese hamster ovary cells expressing human D(3) receptors and potently antagonized R(+)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphtalene HBr (7-OH-DPAT)-induced suppression of cAMP formation (pK(b) 9.57). In these functional assays, cariprazine showed similar (D(2)) or higher (D(3)) antagonist-partial agonist affinity and greater (3- to 10-fold) D(3) versus D(2) selectivity compared with aripiprazole. In in vivo turnover and biosynthesis experiments, cariprazine demonstrated D(2)-related partial agonist and antagonist properties, depending on actual dopaminergic tone. The antagonist-partial agonist properties of cariprazine at D(3) and D(2) receptors, with very high and preferential affinity to D(3) receptors, make it a candidate antipsychotic with a unique pharmacological profile among known antipsychotics.
Kiss
Béla
B
Department of Molecular Pharmacology, Gedeon Richter Plc., P.O. Box 27., Budapest, H-1475 Hungary. b.kiss@richter.hu
Horváth
Attila
A
Némethy
Zsolt
Z
Schmidt
Eva
E
Laszlovszky
István
I
Bugovics
Gyula
G
Fazekas
Károly
K
Hornok
Katalin
K
Orosz
Szabolcs
S
Gyertyán
István
I
Agai-Csongor
Eva
E
Domány
György
G
Tihanyi
Károly
K
Adham
Nika
N
Szombathelyi
Zsolt
Z
D015107:4-Butyrolactone / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D004298:Dopamine / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D054333:Drug Partial Agonism; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000096:biosynthesis; D008297:Male; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism
D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D007295:Inositol Phosphates; D010879:Piperazines; D015363:Quinolones; D050637:Receptors, Dopamine D3; D011969:Receptors, Histamine H1; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D012701:Serotonin; D000068180:Aripiprazole; D012110:Reserpine; D000242:Cyclic AMP; C533287:cariprazine; D015107:4-Butyrolactone; D004298:Dopamine