- Design, synthesis and evaluation of quinolinone derivatives containing dithiocarbamate moiety as multifunctional AChE inhibitors for the treatment of Alzheimer’s disease
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A series of novel quinolinone derivatives bearing dithiocarbamate moiety were designed and synthesised as multifunctional AChE inhibitors for the treatment of AD. Most of these compounds exhibited strong and clearly selective inhibition to eeAChE. Among them, compound 4c was identified as the most potent inhibitor to both eeAChE and hAChE (IC50 = 0.22 μM for eeAChE; IC50 = 0.16 μM for hAChE), and it was also the best inhibitor to AChE-induced Aβ aggregation (29.02% at 100 μM) and an efficient inhibitor to self-induced Aβ aggregation (30.67% at 25 μM). Kinetic and molecular modelling studies indicated that compound 4c was a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4c had good ability to cross the BBB, showed no toxicity on SH-SY5Y neuroblastoma cells and was well tolerated in mice at doses up to 2500 mg/kg (po).
- Fu, Jie,Bao, Fengqi,Gu, Min,Liu, Jing,Zhang, Zhipeng,Ding, Jiaoli,Xie, Sai-Sai,Ding, Jinsong
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- Acetylcholinesterase inhibition of diversely functionalized quinolinones for alzheimer’s disease therapy
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In this communication, we report the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (QN1-19) and 13 dihydroquinolinones (DQN1-13) designed as potential multitarget small molecules (MSM) for Alzheimer’s disease therapy. Contrary to our expectations, none of them showed significant human recombinant MAO inhibition, but compounds QN8, QN9, and DQN7 displayed promising human recombinant acetylcholinesterase (hrAChE) and butyrylcholinesterase (hrBuChE) inhibition. In particular, molecule QN8 was found to be a potent and quite selective non-competitive inhibitor of hrAChE (IC50 = 0.29 μM), with Ki value in nanomolar range (79 nM). Pertinent docking analysis confirmed this result, suggesting that this ligand is an interesting hit for further investigation.
- Bautista-Aguilera, óscar M.,Ismaili, Lhassane,Chioua, Mourad,Andrys, Rudolf,Schmidt, Monika,Bzonek, Petr,Martínez-Grau, María ángeles,Beadle, Christopher D.,Vetman, Tatiana,López-Mu?oz, Francisco,Iriepa, Isabel,Refouvelet, Bernard,Musilek, Kamil,Marco-Contelles, José
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- 2-Phenylcyclopropylmethylamine Derivatives as Dopamine D2Receptor Partial Agonists: Design, Synthesis, and Biological Evaluation
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Partial agonist activity at the dopamine D2 receptor (D2R) is the primary pharmacological feature of the third-generation antipsychotics─aripiprazole, brexpiprazole, and cariprazine. However, all these drugs share a common phenyl-piperazine moiety as the primary pharmacophore. In this study, we designed and synthesized a series of novel compounds based on the 2-phenylcyclopropylmethylamine (PCPMA) scaffold and studied their pharmacological activity at the D2R. A number of potent D2R partial agonists were identified through binding affinity screening and functional activity profiling in both G protein and β-arrestin assays. The structure-functional activity relationship results showed that the spacer group is crucial for fine-tuning the intrinsic activity of these compounds. Compounds (+)-14j and (+)-14l showed good pharmacokinetic properties and an unexpected selectivity against the serotonin 2A (5-HT2A) receptor. Preliminary suppressive effects in a mouse hyperlocomotion model proved that these PCPMA-derived D2R partial agonists are effective as potential novel antipsychotics.
- Cheng, Jianjun,Fan, Luyu,Liu, Ruiquan,Tan, Liang,Wang, Huan,Wang, Sheng,Yan, Wenzhong,Yu, Jing
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supporting information
p. 17239 - 17258
(2021/12/06)
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- FUNCTIONALLY SELECTIVE LIGANDS OF DOPAMINE D2 RECEPTORS
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The present invention relates to novel functionally selective ligands of dopamine D2 receptors, including agonists, antagonists, and inverse agonists. The invention further relates to the use of these compounds for treating central nervous system disorders related to D2 receptors.
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