Distinct functional profiles of aripiprazole and olanzapine at RNA edited human 5-HT2C receptor isoforms

Abstract In this study we have functionally characterized aripiprazole (OPC-14597; 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy-3,4-dihydro-2-(1H)-quinolinone), the prototype of a new generation antipsychotic drug termed dopamine–serotonin-system stabilizer, in cells expressing 5-hydroxytryptamine2 (5-HT 2 ) receptor subtypes in comparison with olanzapine. In Chinese hamster ovary (CHO) cells stably expressing 5-HT 2 receptors, aripiprazole displayed a dual agonist/antagonist profile for 5-HT 2C receptor (VNI isoform) mediated calcium signaling (EC 50 1070 nM, IC 50 281 nM). It exhibited no appreciable 5-HT 2A or 5-HT 2B agonism, whereas it antagonized 5-HT-stimulated calcium increase at either 5-HT 2A or 5-HT 2B receptor expressed in CHO cells (IC 50 s of 369 and 0.46 nM, respectively). In comparison, olanzapine was devoid of agonism but was an antagonist at all three subtypes, with a potency rank order of 5-HT 2A (IC 50 , 2.5 nM) > 5-HT 2B (47 nM) > 5-HT 2C (69 nM). In human embryonic kidney (HEK) cells transiently expressing 5-HT 2C receptor isoforms, aripiprazole exhibited full agonism at the unedited INI, but partial agonism at the partially edited VNI and fully edited VSV isoforms (EC 5O s of 571, 1086 and 2099 nM, respectively). A partial antagonism was also observed for aripiprazole at the two edited isoforms (IC 50 s of 1138 and 1000 nM, respectively). In contrast, while lacking agonist activity at the VNI and VSV, olanzapine showed inverse agonism at the INI isoform (IC 50 594 nM), reaching a maximal attenuation of 20%. In addition, olanzapine was a full antagonist at all three isoforms, with a rank order of potency of VNI (IC 50 , 79 nM) > VSV (101 nM) > INI (3856 nM). The modest 5-HT 2A antagonism and 5-HT 2C partial agonism, along with reported D 2 and 5-HT 1A partial agonism, may allow aripiprazole to stabilize the disturbed dopamine–serotonin interplay in schizophrenia with a moderate yet adequate pharmacological intervention. 5-HT 2C agonism may also underlie the minimal weight gain seen with aripiprazole.