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

• Published in: European journal of pharmacology Vol. 517; no. 3; pp. 165 - 173
• Main Authors: JORDAN, Shaun, RUOYAN CHEN, KOPRIVICA, Vuk, HAMILTON, Ronald, WHITEHEAD, Richard E, TOTTORI, Katsura, KIKUCHI, Tetsuro
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 11-07-2005
• Subjects: 8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology; Animals; Antidepressive Agents - pharmacology; Autoradiography; Binding, Competitive - drug effects; Biological and medical sciences; Buspirone - pharmacology; Cell Membrane - drug effects; Cell Membrane - metabolism; CHO Cells; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Frontal Lobe - drug effects; Frontal Lobe - metabolism; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Hippocampus - drug effects; Hippocampus - metabolism; Humans; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Pindolol - pharmacology; Piperazines - pharmacology; Pyridines - pharmacology; Quinolones - pharmacology; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A - metabolism; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Serotonin Antagonists - pharmacology; Serotonin Receptor Agonists - pharmacology; Sulfur Radioisotopes; Mood disorder; Human; Rat; Serotonin; Psychotropic; Rodentia; Depression; In vitro; Vertebrata; Mammalia; 5-HT1A Serotonine receptor; Animal; Neurotransmitter; Antidepressant agent; OPC-14523
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2005.05.035

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 microM) increased guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]GTPgammaS) binding to 5-HT1A receptor-containing regions of rat brain tissue sections (approximately 53% of the effect of 1 microM (+)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]GTPgammaS binding to membranes from rat hippocampus (pEC50=7.60+/-0.23, Emax=41.1% of the effect of 10 microM (+)8-OH-DPAT), human frontal cortex (pEC50=7.89+/-0.08; Emax=64% of the effect of 10 microM (+)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 microM 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.