100721-33-3Relevant academic research and scientific papers
Design, Synthesis, and Structure-Activity Relationship Studies of Novel Indolyalkylpiperazine Derivatives as Selective 5-HT1A Receptor Agonists
Wang, Wenli,Zheng, Lan,Li, Wei,Zhu, Chen,Peng, Weiqing,Han, Bing,Fu, Wei
, p. 235 - 248 (2020/02/18)
5-HT1A receptor (5-HT1AR) agonists have been implicated in the treatment of a variety of central nervous system (CNS) diseases such as depression and anxiety, et al. Based on our previously found compound FW01 (Ki = 51 ± 16 nM) obtained by virtual screening, a series of FW01 derivatives were designed and synthesized by the modification of the amide tail group as well as indole headgroup of FW01. SAR exploration found that amide tail group and indole headgroup play pivotal roles in determining the binding affinity and selectivity on dopamine and serotonin receptor subtypes. Among all tested compounds, 9_24 has a Ki value of 5 ± 0.6 nM with a good selectivity toward 5-HT1AR. The [35S] GTPγS assay showed that 9_24 is a full agonist toward 5-HT1AR with an EC50 value of 0.059 nM, which shows 266.2 and 146.4-fold selectivity to 5-HT2A and D3 respectively. Molecular dynamics simulations and molecular docking studies with 5-HT1AR-9_24 were performed to disclose the mechanism of its high activity and selectivity. Finally, a detailed stepwise 9_24 induced signal transduction mechanism of 5-HT1AR is proposed.
Higher-Affinity Agonists of 5-HT1AR Discovered through Tuning the Binding-Site Flexibility
Lian, Peng,Li, Linlang,Geng, Chuanrong,Zhen, Xuechu,Fu, Wei
, p. 1616 - 1627 (2015/09/01)
Discovery of high-affinity and high-selectivity agonists of 5-HT1AR has become very attractive due to their potential therapeutic effects on multiple 5-HT1AR-related psychological and neurological problems. On the basis of our previously designed lead compound FW01 (Ki = 51.9 nM, denoted as 9a in the present study), we performed large-scale molecular dynamics simulations and molecular docking operations on 5-HT1AR-9a binding. We found the flip-packing events for the headgroup of 9a, and we also found that its tail group could bind flexibly at the agonist-binding site of 5-HT1AR. By finely tuning the flip-packing phenomenon of the 9a headgroup and tuning the binding flexibility of 9a tail group, we virtually designed a series of new 9a derivatives through molecular docking operations and first-principles calculations and predicted that these newly designed 9a derivatives should be higher-affinity agonists of 5-HT1AR. The computational predictions on the new 9a derivatives have been confirmed by our wet-experimental studies as chemical synthesis, binding affinity assays, and agonistic-function assays. The consistency between our computational design and wet-experimental measurements has led to our discovery of higher-affinity agonists of 5-HT1AR, with ～50-fold increase in receptor-binding affinity and ～25-fold improvements in agonistic function. In addition, our newly designed 5-HT1AR agonists showed very high selectivity of 5-HT1AR over subtype 5-HT2AR and also over three subtypes of dopamine receptors (D1, D2, and D3). (Graph Presented).
Design, synthesis, and evaluation of indolebutylamines as a novel class of selective dopamine D3 receptor ligands
Du, Peng,Xu, Lili,Huang, Jiye,Yu, Kunqian,Zhao, Rui,Gao, Bo,Jiang, Hualiang,Zhao, Weili,Zhen, Xuechu,Fu, Wei
, p. 326 - 335 (2013/09/12)
A series of indolebutylamine derivatives were designed, synthesized, and evaluated as a novel class of selective ligands for the dopamine 3 receptor. The most potent compound 11q binds to dopamine 3 receptor with a Ki value of 124 nm and displays excellent selectivity over the dopamine 1 receptor and dopamine 2 receptor. Investigation based on structural information indicates that site S182 located in extracellular loop 2 may account for high selectivity of compounds. Interaction models of the dopamine 3 receptor-11q complex and structure-activity relationships were discussed by integrating all available experimental and computational data with the eventual aim to discover potent and selective ligands to dopamine 3 receptor.
Discovery of novel N -phenylphenoxyacetamide derivatives as EthR inhibitors and ethionamide boosters by combining high-throughput screening and synthesis
Flipo, Marion,Willand, Nicolas,Lecat-Guillet, Nathalie,Hounsou, Candide,Desroses, Matthieu,Leroux, Florence,Lens, Zoé,Villeret, Vincent,Wohlk?nig, Alexandre,Wintjens, René,Christophe, Thierry,Kyoung Jeon, Hee,Locht, Camille,Brodin, Priscille,Baulard, Alain R,Déprez, Benoit
supporting information; experimental part, p. 6391 - 6402 (2012/10/07)
In this paper, we describe the screening of a 14640-compound library using a novel whole mycobacteria phenotypic assay to discover inhibitors of EthR, a transcriptional repressor implicated in the innate resistance of Mycobacterium tuberculosis to the second-line antituberculosis drug ethionamide. From this screening a new chemical family of EthR inhibitors bearing an N-phenylphenoxyacetamide motif was identified. The X-ray structure of the most potent compound crystallized with EthR inspired the synthesis of a 960-member focused library. These compounds were tested in vitro using a rapid thermal shift assay on EthR to accelerate the optimization. The best compounds were synthesized on a larger scale and confirmed as potent ethionamide boosters on M. tuberculosis-infected macrophages. Finally, the cocrystallization of the best optimized analogue with EthR revealed an unexpected reorientation of the ligand in the binding pocket.
Triazoloamides as potent γ-secretase modulators with reduced hERG liability
Fischer, Christian,Zultanski, Susan L.,Zhou, Hua,Methot, Joey L.,Shah, Sanjiv,Nuthall, Hugh,Hughes, Bethany L.,Smotrov, Nadja,Hill, Armetta,Szewczak, Alexander A.,Moxham, Christopher M.,Bays, Nathan,Middleton, Richard E.,Munoz, Benito,Shearman, Mark S.
scheme or table, p. 3140 - 3146 (2012/06/04)
Synthesis and SAR studies of novel aryl triazoles as gamma secretase modulators (GSMs) are presented in this communication. Starting from our aryl triazole leads, optimization studies were continued and the series progressed towards novel amides and lactams. Triazole 57 was identified as the most potent analog in this series, displaying single-digit nanomolar Aβ42 IC 50 in cell-based assays and reduced affinity for the hERG channel.
ABCA-1 ELEVATING COMPOUNDS
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, (2008/06/13)
The present invention provides compounds that elevate cellular expression of the ABCA-1 gene, promoting cholesterol efflux from cells and increasing HDL levels in the plasma of a mammal, in particular humans. The compounds are useful for treating coronary
COMPOUNDS OF THE FORMU;A R1-X-Y-Z-NR2R3 AS ABCA-1 ELEVATING AGENTS AGAINST CAD OR ATHEROSCLEROSIS
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Page 30, (2010/02/05)
The present invention provides compounds that elevate cellular expression of the ABCA-1 gene, promoting cholesterol efflux from cells and increasing HDL levels in the plasma of a mammal, in particular humans. The compounds are useful for treating coronary
ABCA-1 Elevating compounds
-
, (2008/06/13)
The present invention provides compounds that elevate cellular expression of the ABCA-1 gene, promoting cholesterol efflux from cells and increasing HDL levels in the plasma of a mammal, in particular humans. The compounds are useful for treating coronary
