title: Novel quinazolinone derivatives as 5-HT7 receptor ligands.
abstract: 5-HT(7) receptor antagonists generated antidepressant-like effects in animal model and the involvement of the 5-HT(7) receptor in other pathophysiological mechanisms such as thermoregulation, learning and memory, and sleep has been highlighted by various studies. As one of our efforts to discover a new type of 5-HT(7) receptor antagonists, we here report on the synthesis and binding affinities to the 5-HT(7) receptor of the quinazolinone library 1, which was designed with various substituents (X, Y, R(1), and R(2)) on the aromatic rings and different carbon chain length. Total 85 compounds of the quinazolinone library 1 were synthesized and the binding affinities of all the synthesized compounds were obtained by radioligand binding assay for the 5-HT(7) receptor. Among the 85 compounds, 24 compounds show very good binding affinities with IC(50) values below 100 nM. Mainly the compounds with IC(50) values below 100 nM have o-OMe or o-OEt as R(2) substituent. The compound with the best binding affinity is 1-68 of which the IC(50) value is 12 nM. In in vivo animal study, some synthesized compounds really have the antidepressant activity in the forced swimming test in mice.
authors: Life Sciences Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea.
authors: Yong Ho
authors: YH
authors: Na
authors: Sung Ho
authors: SH
authors: Hong
authors: Jung Hyang
authors: JH
authors: Lee
authors: Woo-Kyu
authors: WK
authors: Park
authors: Du-Jong
authors: DJ
authors: Baek
authors: Hun Yeong
authors: HY
authors: Koh
authors: Yong Seo
authors: YS
authors: Cho
authors: Hyunah
authors: H
authors: Choo
authors: Ae Nim
authors: AN
authors: Pae
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D003863:Depression / Q000188:drug therapy; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D018377:Neurotransmitter Agents / Q000138:chemical synthesis / Q000737:chemistry; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013550:Swimming
chemical_list: D000928:Antidepressive Agents; D008024:Ligands; D018377:Neurotransmitter Agents; D052999:Quinazolinones; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor