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Cao, Yongkai,Sun, Ningning,Zhang, Jiumei,Liu, Zhiguo,Tang, Yi-zhe,Wu, Zhengzhi,Kim, Kyeong-Man,Cheon, Seung Hoon The Royal Society of Chemistry 2018 MedChemComm Vol.9 No.9
<P>The dopamine D3 receptor (D3R) is a proven therapeutic target for the treatment of neurological and neuropsychiatric disorders. In particular, D3R-selective ligands that can eliminate side effects associated with dopamine D2 receptor (D2R) therapeutics have been validated. However, the high homology in signaling pathways and the sequence similarity between D2R and D3R have rendered the development of D3R-selective ligands challenging. Herein, we designed and synthesized a series of piperazine-phthalimide bitopic ligands based on a fragment-based and molecular docking inspired design. Compound 9i was identified as the most selective D3R ligand among these bitopic ligands. Its selectivity was improved compared to reference compounds 1 and 2 by 9- and 2-fold, respectively, and it was 21-fold more potent than compound 2. Molecular docking demonstrated that the orientation of Leu<SUP>2.64</SUP> and Phe<SUP>7.39</SUP> and the packing at the junction of helices may affect the specificity for D3R over D2R. Functional evaluation revealed that D3R-selective ligand 9i displayed a subpicomolar agonist activity at D3R with a 199-fold increase in potency compared to quinpirole. These results may be useful for the fragment-based design of bitopic compounds as selective D3R ligands.</P>
Synthesis and evaluation of arylpiperazine-reverse amides as biased dopamine D3 receptor ligands
( Yongkai Cao ),( Suresh Paudel ),( Xiaowei Zhang ),( Kyeong-man Kim ),( Seung Hoon Cheon ) 전남대학교 약품개발연구소 2015 약품개발연구지 Vol.24 No.-
The dopamine D3 receptor (D3R) preferential ligands have been universally adopted as a strategy for the treatment of drug addiction and other neuropsychiatric disorders due to fewer side effects. However, the high sequence homology between D3R and the D2 receptor (D2R) challenges the development of D3R-biased compounds. Herein. we design and synthesize a novel series of reverse amide-piperazine hybrid ligands and evaluate their biological affinities in vitro. Compound 4d was found to be the most potent D3R-selective ligand among these hybrid derivatives. Molecular modeling revealed that extracellular loop 1 (EL1) and loop 2 (EL2) of D3R together likely contribute to D3R selectivity over D2R. In particular. Gly94 in EL1 of D3R may act as a molecular determinant for D3R specificity.
A Novel Partial PPARα/γ Dual Agonist SN159 Improves Insulin Sensitivity
정유정,Yongkai Cao,Suresh Paudel,김기현,윤구,천승훈,Jee-Young Lee,김수남,김용기 대한화학회 2016 Bulletin of the Korean Chemical Society Vol.37 No.2
We here demonstrate that (E)-1-(3-aminophenyl)-3-(5-bromo-4-hydroxy-2-methoxyphenyl)prop-2-en-1-one (SN159) is a novel peroxisome proliferator-activated receptor (PPAR) partial agonist that improves insulin sensitivity. SN159 interacted directly with PPARα and PPARγ, which were confirmed by LanthaScreen ligand binding assay and molecular docking study. SN159 treatment leads to a significant improvement of insulin sensitivity, resulting in enhancing glucose uptake in muscle cells. SN159 stimulated adipogenic differentiation of 3T3-L1 preadipocytes, however, the effects were much weaker than those of PPARγ agonist troglitazone. In parallel, SN159 increased weakly the transcriptional activities of PPARα/γ, compared to the positive control. Furthermore, PPARγ activation and adipogenic differentiation by troglitazone were significantly reduced by treatment with SN159, indicating that SN159 is a partial agonist of PPARs. SN159 was able to enhance fatty acid oxidation and glucose utilization through the dual activation of PPARα/γ. Taken together, these results suggest that SN159 is a novel PPAR partial agonist, which can be used as potential therapeutic agents against type 2 diabetes and related metabolic disorders by enhancing glucose and lipid metabolism.
( Suresh Paudel ),( Yongkai Cao ),( Shuohan Guo ),( Byeongkwan An ),( Kyeong-man Kim ),( Seung Hoon Cheon ) 전남대학교 약품개발연구소 2015 약품개발연구지 Vol.24 No.-
A series of 4-benzylpiperidine carboxamides were designed and synthesized. and tested for their dual(serotonin and norepinephrine) reuptake inhibition. The synthesis of 4-benzylpiperidine carboxamides involved two main steps: amidation and substitution. Derivatives with 3 carbon linker displayed better activity than with 2 carbon linker. 4-Biphenyl- and 2-naphthyl-substituted derivatives 7e and 7j showed greater dual reuptake inhibition than standard drug venlafaxine HCI.
Concise synthesis of licochalcone C and its regioisomer, licochalcone H
Zengtao Wang,Yongkai Cao,Suresh Paudel,윤구,천승훈 대한약학회 2013 Archives of Pharmacal Research Vol.36 No.12
Licochalone C (7a) is a retrochalcone isolatedfrom Glycyrrhiza inflata, which shows potent antioxidantproperties and inhibition of bacterial growth and cellularrespiration. Biological studies have suggested that licochalconeC attenuates the lipopolysaccharide and interferongammainduced inflammatory response by decreasing theexpression and activity of inducible nitric oxide synthaseand modulating the antioxidant network activity of superoxidedismutase, catalase, and glutathione peroxidaseactivity. Licochalcone C also inhibits NADH-cytochrome Creductase in the membrane fraction of Micrococcus luteus. Since pharmacological activity studies of licochalcone C areongoing and the yield of the compound is poor from naturalproduct, we report a concise four step synthesis of licochalconeC (7a) and its regioisomer, tentatively called licochalconeH (7b), by employing acid-mediated Claisen-Schmidt condensation as a key step with 6 and 20 % overallyield, respectively.