Synthesis and evaluation of novel 2,3-dihydrobenzo[b][1,4]dioxin- and indolealkylamine derivatives as potential antidepressants.
A series of 2,3-dihydrobenzo[b][1,4]dioxin- and indolealkylamine derivatives were synthesized and the target compounds were evaluated for their binding affinities at the 5-HT1A receptor and serotonin transporter. Antidepressant-like activities of the compounds were screened using the tail suspension and forced swim tests in mice. Preliminary results indicated that the target compounds exhibited high binding affinities at the 5-HT1A receptor and serotonin transporter, and produced marked antidepressant-like effects. The best example from this study, compound 5, exhibited high binding affinities for the 5-HT1A receptor (Ki  = 96 nM) and serotonin transporter (Ki  = 9.8 nM). The intrinsic activity of compound 5 showed agonistic property to the 5-HT1A receptor and inhibition of the 5-HT transporter. Furthermore, compound 5 exhibited greater antidepressant efficacy than fluoxetine and showed acceptable pharmacokinetic properties.
Department of Biomedical Engineering, Systems Biology Theme, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
Songlin
S
Wang
Yin
Y
Chen
Xinghua
X
Liu
Xiangqing
X
Xu
Xin
X
Liu
Bi-Feng
BF
Liu
Guisen
G
Zhang
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D003863:Depression / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism / Q000523:psychology; D004147:Dioxins / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000138:chemical synthesis / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013550:Swimming
D000928:Antidepressive Agents; D004147:Dioxins; D005473:Fluoxetine; D007211:Indoles; D016601:RNA-Binding Proteins; D044282:Receptor, Serotonin, 5-HT1A; D058825:Serotonin 5-HT1 Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C482440:Sert1 protein, rat
2,3-Dihydrobenzo[b][1,4]dioxin; Antidepressants; Dual 5-HT1A/5-HT transporter activity; Indolealkylamine