Novel quinazolinone derivatives as 5-HT7 receptor ligands.
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.
Na
Yong Ho
YH
Life Sciences Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea.
Hong
Sung Ho
SH
Lee
Jung Hyang
JH
Park
Woo-Kyu
WK
Baek
Du-Jong
DJ
Koh
Hun Yeong
HY
Cho
Yong Seo
YS
Choo
Hyunah
H
Pae
Ae Nim
AN
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
D000928:Antidepressive Agents; D008024:Ligands; D018377:Neurotransmitter Agents; D052999:Quinazolinones; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor