title: Further optimization of novel pyrrole 3-carboxamides for targeting serotonin 5-HT(2A), 5-HT(2C), and the serotonin transporter as a potential antidepressant.
abstract: 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.
authors.affiliation: Research Center, Green Cross Corporation, Giheung-Gu, Yongin, Republic of Korea.
authors.forename: Suk Youn
authors.initials: SY
authors.lastname: Kang
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Park
authors.forename: Woo-Kyu
authors.initials: WK
authors.lastname: Park
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Gildon
authors.initials: G
authors.lastname: Choi
authors.forename: Myung Eun
authors.initials: ME
authors.lastname: Jung
authors.forename: Hee Jeong
authors.initials: HJ
authors.lastname: Seo
authors.forename: Min Ju
authors.initials: MJ
authors.lastname: Kim
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Kim
authors.forename: Jinhwa
authors.initials: J
authors.lastname: Lee
mesh_terms: 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*
chemical_list: D000928:Antidepressive Agents; D010879:Piperazines; D011758:Pyrroles; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D050486:Serotonin Plasma Membrane Transport Proteins