In vitro profile of the antidepressant candidate OPC-14523 at rat and human 5-HT1A receptors

This study determined the in vitro functional profile of 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2-quinolinone monomethanesulfonate (OPC-14523) at rat and human serotonin (5-HT) 5-HT1A receptors and binding affinity of OPC-14523 at human frontocortical 5-HT1A receptors. OPC-14523 (1 μM) increased guanosine-5′-O-(3-[35S]thio)-triphosphate ([35S]GTPγS) binding to 5-HT1A receptor-containing regions of rat brain tissue sections (∼53% of the effect of 1 μM (+)8-hydroxy-2-(di-n-propylamino)tetralin ((+)8-OH-DPAT) that were blocked by the selective 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY-100635). OPC-14523 also behaved as a partial agonist in its stimulation of [35S]GTPγS binding to membranes from rat hippocampus (pEC50 = 7.60 ± 0.23, Emax = 41.1% of the effect of 10 μM (+)8-OH-DPAT), human frontal cortex (pEC50 = 7.89 ± 0.08; Emax = 64% of the effect of 10 μM (+)8-OH-DPAT), and Chinese Hamster Ovary cells expressing cloned human 5-HT1A receptors (pEC50 = 8.0 ± 0.11; Emax = 85.5% of the effect of 10 μM 5-HT), and all of these effects of OPC-14523 were blocked by WAY-100635. Taken together, these data support the development of OPC-14523 as an antidepressant whose mechanism of action involves potent partial agonist activity at 5-HT1A receptors.