Kim, Youngjae Tae, Jinsung Lee, Kangho Rhim, Hyewhon Choo, Il Han Cho, Heeyeong Park, Woo-Kyu Keum, Gyochang Choo, Hyunah 2024-01-20T09:01:37Z 2024-01-20T09:01:37Z 2021-09-02 2014-09-01 0968-0896 https://pubs.kist.re.kr/handle/201004/126368 5-HT7 receptor (5-HT7R) is a promising target for the treatment of depression and neuropathic pain. 5-HT7R antagonists exhibited antidepressant effects, while the agonists produced strong anti-hyperalgesic effects. In our efforts to discover selective 5-HT7R antagonists or agonists, N-biphenylylmethyl 2-methoxyphenylpiperazinylalkanamides 1 were designed, synthesized, and biologically evaluated against 5-HT7R. Among the synthesized compounds, N-2'-chlorobiphenylylmethyl 2-methoxyphenylpiperazinyl-pentanamide 1-8 showed the best binding affinity with a K-i value of 8.69 nM and it was verified as a novel antagonist according to functional assays. The compound 1-8 was very selective over 5-HT1DR, 5-HT2AR, 5-HT3R, 5-HT5AR and 5-HT6R and moderately selective over 5-HT1AR, 5-HT1BR and 5-HT2CR. The novel 5-HT7R antagonist 1-8 exhibited an antidepressant effect at a dose of 25 mg/kg in the forced swimming test in mice and showed a U-shaped dose-response curve which typically appears in 5-HT7R antagonists such as SB-269970 and lurasidone. (C) 2014 Elsevier Ltd. All rights reserved. English PERGAMON-ELSEVIER SCIENCE LTD SEROTONIN RECEPTOR MOLECULAR-CLONING PHARMACOLOGICAL BLOCKADE NUCLEUS SUPPRESSES BEHAVIORAL DESPAIR SPINAL 5-HT7 REM-SLEEP AGONIST ACTIVATION POTENT Novel N-biphenyl-2-ylmethyl 2-methoxyphenylpiperazinylalkanamides as 5-HT7R antagonists for the treatment of depression Article 10.1016/j.bmc.2014.07.026 1 BIOORGANIC & MEDICINAL CHEMISTRY, v.22, no.17, pp.4587 - 4596 BIOORGANIC & MEDICINAL CHEMISTRY 22 17 4587 4596 scie scopus 000341293300007 2-s2.0-84906939234 Biochemistry & Molecular Biology Chemistry, Medicinal Chemistry, Organic Biochemistry & Molecular Biology Pharmacology & Pharmacy Chemistry Article SEROTONIN RECEPTOR MOLECULAR-CLONING PHARMACOLOGICAL BLOCKADE NUCLEUS SUPPRESSES BEHAVIORAL DESPAIR SPINAL 5-HT7 REM-SLEEP AGONIST ACTIVATION POTENT Serotonin receptor 5-HT7R Antagonist Depression Antidepressant