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Paudel, Suresh,Acharya, Srijan,Yoon, Goo,Kim, Kyeong-Man,Cheon, Seung Hoon Pergamon 2017 Bioorganic & medicinal chemistry Vol.25 No.7
<P><B>Abstract</B></P> <P>Monoamine transporters regulate the concentration of monoamine neurotransmitters, which are essential for vital physiological processes, and their dysfunction can cause several central nervous system diseases. Monoamine transporters currently appear to be the potential target in the management of these disorders. In this study, homologation and bioisosterism techniques have been used in the designing of new 1,4-disubstituted piperazines and piperidines. These derivatives were synthesized and evaluated as potential triple reuptake inhibitors for studying the structure-activity relationships. The most advanced compound, 1-(4-(5-benzhydryl-1<I>H</I>-tetrazol-1-yl)butyl)-4-(3-phenylpropyl)piperazine (<B>2i</B>), was able to inhibit monoamine neurotransmitter reuptake in an <I>in vitro</I> test (IC<SUB>50</SUB> =158.7nM for 5-HT, 99nM for NE and 97.5nM for DA). These novel potent triple reuptake inhibitor-based 1,4-disubstituted piperazine and piperidine scaffolds deserve further systematic optimization and pharmacological evaluation.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Paudel Suresh,Wang Shuji,Kim Eunae,Kundu Dooti,Min Xiao,Shin Chan Young,Kim Kyeong-Man 한국응용약물학회 2022 Biomolecules & Therapeutics(구 응용약물학회지) Vol.30 No.2
Tetrazoles were designed and synthesized as potential inhibitors of triple monoamine neurotransmitters (dopamine, norepinephrine, serotonin) reuptake based on the functional and docking simulation of compound 6 which were performed in a previous study. The compound structure consisted of a tetrazole-linker (n)-piperidine/piperazine-spacer (m)-phenyl ring, with tetrazole attached to two phenyl rings (R1 and R2). Altering the carbon number in the linker (n) from 3 to 4 and in the spacer (m) from 0 to 1 increased the potency of serotonin reuptake inhibition. Depending on the nature of piperidine/piperazine, the substituents at R1 and R2 exerted various effects in determining their inhibitory effects on monoamine reuptake. Docking study showed that the selectivity of tetrazole for different transporters was determined based on multiple interactions with various residues on transporters, including hydrophobic residues on transmembrane domains 1, 3, 6, and 8. Co-expression of dopamine transporter, which lowers dopamine concentration in the biophase by uptaking dopamine into the cells, inhibited the dopamine-induced endoctytosis of dopamine D2 receptor. When tested for compound 40 and 56, compound 40 which has more potent inhibitory activity on dopamine reuptake more strongly disinhibited the inhibitory activity of dopamine transporter on the endocytosis of dopamine D2 receptor. Overall, we identified candidate inhibitors of triple monoamine neurotransmitter reuptake and provided a theoretical background for identifying such neurotransmitter modifiers for developing novel therapeutic agents of various neuropsychiatric disorders.
( Suresh Paudel ),( Eunae Kim ),( Anlin Zhu ),( Srijan Acharya ),( Xiao Min ),( Seung Hoon Cheon ),( Kyeong-man Kim ) 한국응용약물학회 2021 Biomolecules & Therapeutics(구 응용약물학회지) Vol.29 No.4
In this study, we determined the effect of 24 different synthetic 4-benzylpiperidine carboxamides on the reuptake of serotonin, norepinephrine, and dopamine (DA), and characterized their structure-activity relationship. The compounds with a two-carbon linker inhibited DA reuptake with much higher potency than those with a three-carbon linker. Among the aromatic ring substituents, biphenyl and diphenyl groups played a critical role in determining the selectivity of the 4-benzylpiperidine carboxamides toward the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. Compounds with a 2-naphthyl ring were found to exhibit a higher degree of inhibition on the norepinephrine transporter (NET) and SERT than those with a 1-naphthyl ring. A docking simulation using a triple reuptake inhibitor 8k and a serotonin/norepinephrine reuptake inhibitor 7j showed that the regions spanning transmembrane domain (TM)1, TM3, and TM6 form the ligand binding pocket. The compound 8k bound tightly to the binding pocket of all three monoamine reuptake transporters; however, 7j showed poor docking with DAT. Co-expression of DAT with the dopamine D<sub>2</sub> receptor (D<sub>2</sub>R) significantly inhibited DA-induced endocytosis of D<sub>2</sub>R probably by reuptaking DA into the cells. Pretreatment of the cells with 8f, which is one of the compounds with good inhibitory activity on DAT, blocked DAT-induced inhibition of D<sub>2</sub>R endocytosis. In summary, this study identified critical structural features contributing to the selectivity of a molecule for each of the monoamine transporters, critical residues on the compounds that bound to the transporters, and the functional role of a DA reuptake inhibitor in regulating D<sub>2</sub>R function.
( 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.
Paudel, Suresh,Min, Xiao,Acharya, Srijan,Khadka, Daulat Bikram,Yoon, Goo,Kim, Kyeong-Man,Cheon, Seung Hoon Pergamon 2017 Bioorganic & medicinal chemistry Vol.25 No.20
<P><B>Abstract</B></P> <P>Monoamine transporters are important targets in the treatment of various central nervous disorders. Several limitations of traditional reuptake inhibitors, like delayed onset of action, insomnia, and sexual dysfunction, have compelled the search for safer, more effective compounds. In this study, we have sought to identify novel monoamine reuptake inhibitors. Based upon the docking study of compounds that we had reported previously, aromatic rings (A1) were modified to generate a novel series of benzylpiperidine–tetrazoles. Thirty-one compounds were synthesized and evaluated for their triple reuptake inhibition of serotonin, norepinephrine and dopamine. Triple reuptake inhibitor, compound <B>2q</B>, in particular, showed potent serotonin reuptake inhibition, validating our design approach.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Paudel, Suresh,Sun, Ningning,Khadka, Daulat Bikram,Yoon, Goon,Kim, Kyeong-Man,Cheon, Seung Hoon Elsevier 2018 Bioorganic & medicinal chemistry Vol.26 No.14
<P><B>Abstract</B></P> <P>Rational drug design method has been used to generate 4-arylpiperazine carboxamides in an effort to develop safer, more potent and effective monoamine neurotransmitters reuptake inhibitors. Out of twenty-seven synthesized compounds, compound <B>9</B> displayed potent monoamine neurotransmitter reuptake inhibitory activity against HEK cells transfected with hSERT or hNET. A Surflex-Dock docking model of <B>9</B> was also studied.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Paudel, Suresh,Min, Xiao,Acharya, Srijan,Khadka, Daulat Bikram,Yoon, Goon,Kim, Kyeong-Man,Cheon, Seung Hoon Elsevier 2018 Bioorganic & medicinal chemistry Vol.26 No.20
<P><B>Abstract</B></P> <P>Two series of 4-arylpiperazine- and 4-benzylpiperidine naphthyl ethers were designed based on structure-activity relationship (SAR) and docking model of reported monoamine neurotransmitters reuptake inhibitors. The compounds were synthesized in 3-simple steps and their biological activities were evaluated. Several compounds were proven to be potent inhibitors of serotonin and norepinephrine reuptake. Computer docking was performed to study the interaction of the most potent compound <B>35</B> with human serotonin transporter. The results of the analyses suggest that 4-arylpiperazine- and 4-benzylpiperidine naphthyl ethers might be promising antidepressants worthy of further studies.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</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.
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.
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.