Novel Serotonin Antagonist/Serotonin Reuptake Inhibitors (SARI) as Potential Antidepressants

다국어 초록 (Multilingual Abstract)

Serotonin(5-HT), a major neurotransmitter found in the central nervous system(CNS), is also present in many peripheral tissues. Its numerous biological functions are mediated by variety of serotonin receptors. The interaction with these different serotonin receptors constitutes the mechanism of action of many drugs. In particular, type 2 serotonin receptors(5-HT2) mediate the actions of several drugs used in treating diseases such as schizophrenia, feeding disorders, perception, depression, migraines, hypertension, anxiety, hallucinations and gastrointestinal dysfunctions.
A dual serotonin antagonist/serotonin reuptake inhibitor(SARI) is attractive strategy to improve pharmaceutical profile of selective serotonin reuptake inhibitor(SSRI). Sequential virtual screening approach using combined models of pharmacophore and recursive partitioning method applied for identification of novel scaffolds resulted in highly active SARI(1.8~80nM for each receptor). Design, synthesis and biological evaluation were performed for developing antagonists active on 5-HT2a and 5-HT2c receptors with high activity on serotonin transporter at the same time. Small molecule libraries having phthalazinone, isoxazole and oxazole moieties were constructed and evaluted in 5-HT2a, 5-HT2c, and SERT. The hits were evaluted in vivo depression animal model. Some of compounds showed good antidepressive efficacy. The further structural optimizations are in progress.