부산대학교 도서관

The synthesis and structure−activity relationship of a novel series of compounds with combined effects on 5-HT3Aand 5-HT1Areceptors and on the serotonin (5-HT) transporter (SERT) are described. Compound 5m(Lu AA21004) was the lead compound, displaying high affinity for recombinant human 5-HT1A(Ki= 15 nM), 5-HT1B(Ki= 33 nM), 5-HT3A(Ki= 3.7 nM), 5-HT7(Ki= 19 nM), and noradrenergic β1(Ki= 46 nM) receptors, and SERT (Ki= 1.6 nM). Compound 5mdisplayed antagonistic properties at 5-HT3Aand 5-HT7receptors, partial agonist properties at 5-HT1Breceptors, agonistic properties at 5-HT1Areceptors, and potent inhibition of SERT. In conscious rats, 5msignificantly increased extracellular 5-HT levels in the brain after acute and 3 days of treatment. Following the 3-day treatment (5 or 10 (mg/kg)/day) SERT occupancies were only 43% and 57%, respectively. These characteristics indicate that 5mis a novel multimodal serotonergic compound, and 5mis currently in clinical development for major depressive disorder.