Further optimization of novel pyrrole 3-carboxamides for targeting serotonin 5-HT(2A), 5-HT(2C), and the serotonin transporter as a potential antidepressant.
In the continuing search for novel compounds targeting serotonin 5-HT(2A), 5-HT(2C), and serotonin transporter, new arylpiperazine-containing pyrrole 3-carboxamide derivatives were synthesized and evaluated. Based on the lead reported previously, structural modifications regarding N-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)-1,2-dimethyl-5-phenyl-1H-pyrrole-3-carboxamide 5, were accomplished for improvements in not only binding affinity against serotonin receptors and transporter, but also in hERG channel inhibition. Along the line, both the forced swimming tests and spontaneous locomotor activity tests were performed to distinguish between antidepressant activity and false positive results. As potential antidepressant agents, both 2,4-dimethyl-5-phenyl-1H-pyrrole-3-carboxamide and 5-tert-butyl-2-methyl-1H-pyrrole-3-carboxamide derivatives exhibited favorable in vitro and in vivo activities, warranting further investigation around these scaffolds.
Kang
Suk Youn
SY
Research Center, Green Cross Corporation, Giheung-Gu, Yongin, Republic of Korea.
Park
Eun-Jung
EJ
Park
Woo-Kyu
WK
Kim
Hyun Jung
HJ
Choi
Gildon
G
Jung
Myung Eun
ME
Seo
Hee Jeong
HJ
Kim
Min Ju
MJ
Pae
Ae Nim
AN
Kim
Jeongmin
J
Lee
Jinhwa
J
D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*
D000928:Antidepressive Agents; D010879:Piperazines; D011758:Pyrroles; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D050486:Serotonin Plasma Membrane Transport Proteins