Publications by authors named "Srijan Acharya"

22 Publications

  • Page 1 of 1

Clinicopathologic significance and race-specific prognostic association of MYB overexpression in ovarian cancer.

Sci Rep 2021 Jun 18;11(1):12901. Epub 2021 Jun 18.

Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, 36617, USA.

Late diagnosis, unreliable prognostic assessment, and poorly-guided therapeutic planning result in dismal survival of ovarian cancer (OC) patients. Therefore, identifying novel functional biomarker(s) is highly desired for improved clinical management. MYB is an oncogenic transcription factor with emerging functional significance in OC. Here we examined its clinicopathologic significance by immunohistochemistry and TCGA/GTex data analyses. Aberrant MYB expression was detected in 94% of OC cases (n = 373), but not in the normal ovarian tissues (n = 23). MYB was overexpressed in all major epithelial OC histological subtypes exhibiting the highest incidence (~ 97%) and overall expression in serous and mucinous carcinomas. MYB expression correlated positively with tumor grades and stages. Moreover, MYB exhibited race-specific prognostic association. Moderate-to-high MYB levels were significantly associated with both poor overall- (p = 0.02) and progression-free (p = 0.02) survival in African American (AA), but not in the Caucasian American (CA) patients. Consistent with immunohistochemistry data, we observed significantly higher MYB transcripts in OC cases (n = 426) than normal ovary (n = 88). MYB transcripts were significantly higher in all epithelial OC subtypes, compared to normal, and its greater levels predicted poor survival in AA OC, but not CA OC, patients. Thus, MYB appears to be a useful clinical biomarker for prognostication, especially in AA patients.
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http://dx.doi.org/10.1038/s41598-021-92352-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213794PMC
June 2021

Structural Requirements for Modulating 4-Benzylpiperidine Carboxamides from Serotonin/Norepinephrine Reuptake Inhibitors to Triple Reuptake Inhibitors.

Biomol Ther (Seoul) 2021 Jul;29(4):392-398

College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea.

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 receptor (DR) significantly inhibited DA-induced endocytosis of DR 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 DR 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 DR function.
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http://dx.doi.org/10.4062/biomolther.2020.233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255136PMC
July 2021

Zinc and cerium synergistically enhance the mechanical properties, corrosion resistance, and osteogenic activity of magnesium as resorbable biomaterials.

Biomed Mater 2021 Jun 9;16(4). Epub 2021 Jun 9.

Department of Materials Engineering, Indian Institute of Science, C.V. Raman Avenue, Bangalore, 560012, India.

Magnesium and its alloys have the potential to serve as a revolutionary class of biodegradable materials, specifically in the field of degradable implants for orthopedics. However, the corrosion rate of commercially pure magnesium is high and does not match the rate of regeneration of bone tissues. In this work, magnesium alloys containing zinc and cerium, either alone or in combination, were investigated and compared with commercially-pure magnesium as biomaterials. The microstructure, mechanical properties, corrosion resistance, and response of osteoblastswere systematically assessed. Results reveal that alloying with Ce results in grain refinement and weakening of texture. The tensile test revealed that the ternary alloy offered the best combination of elastic modulus (41.1 ± 0.5 GPa), tensile strength (234.5 ± 4.5 MPa), and elongation to break (17.1 ± 0.4%). The ternary alloy was also the most resistant to corrosion (current of 0.85 ± 0.05 × 10A cm) in simulated body fluid than the other alloys. The response of MC3T3-E1 cellsrevealed that the ternary alloy imparts minimal cytotoxicity. Interestingly, the ternary alloy was highly efficient in supporting osteogenic differentiation, as revealed by the expression of alkaline phosphatase and calcium deposition. In summary, the extruded Mg alloy containing both Zn and Ce exhibits a combination of mechanical properties, corrosion resistance, and cell response that is highly attractive for engineering biodegradable orthopedic implants.
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http://dx.doi.org/10.1088/1748-605X/ac0453DOI Listing
June 2021

R (-)-methoxetamine exerts rapid and sustained antidepressant effects and fewer behavioral side effects relative to S (+)-methoxetamine.

Neuropharmacology 2021 08 20;193:108619. Epub 2021 May 20.

School of Pharmacy, Jeonbuk National University, 567 Baekje-daero, Deokjin-gu, Jeonju-si, Jeollabuk-do, 54896 Republic of Korea. Electronic address:

The newfound antidepressant efficacy of ketamine has provided opportunities for the development of new-generation, rapid-acting, glutamate-based antidepressants. We previously identified that methoxetamine (MXE), a ketamine analog, and an N-Methyl-d-aspartate (NMDA) receptor antagonist, produced rapid and sustained antidepressant effects in mice. MXE (R, S (±)-MXE) is a racemic mixture containing equal parts of S (+)-MXE and R (-)-MXE. However, studies have yet to investigate the antidepressant effects of its enantiomers. Here, we examined the potential antidepressant properties and behavioral side effects of S- and R-MXE in mice. Both S- and R-MXE showed significant NMDA receptor affinity and appreciable inhibitory activity on serotonin transporter. Also, S- and R-MXE (10 mg kg) exerted antidepressant effects and increased gamma waves (electroencephalography) but were inhibited by NBQX (an AMPA receptor antagonist). Subsequently, they increased mammalian target of rapamycin phosphorylation and AMPA receptor subunits GluA1 and GluA2 protein levels in the hippocampus or prefrontal cortex. Furthermore, they increased 5HT2a and 5HT2c receptor mRNA levels in the prefrontal cortex, with their antidepressant effects inhibited by ketanserin (a 5HT2a/c receptor antagonist). Taken together, S-MXE and R-MXE elicit antidepressant effects that are probably mediated via glutamatergic and serotonergic mechanisms. Unlike S-MXE, R-MXE did not induce prepulse inhibition deficits, hyperlocomotion, conditioned place preference, and locomotor sensitization, although it acutely altered motor coordination. This suggests that R-MXE induces fewer behavioral side effects and is a safer antidepressant than S-MXE. Overall, this study provides significant implications for future research on the next generation of rapid-acting, glutamate-based antidepressant drugs.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108619DOI Listing
August 2021

Roles of the Functional Interaction between Brain Cholinergic and Dopaminergic Systems in the Pathogenesis and Treatment of Schizophrenia and Parkinson's Disease.

Int J Mol Sci 2021 Apr 21;22(9). Epub 2021 Apr 21.

Pharmacology Laboratory, College of Pharmacy, Chonnam National University, Gwang-Ju 61186, Korea.

Most physiologic processes in the brain and related diseases involve more than one neurotransmitter system. Thus, elucidation of the interaction between different neurotransmitter systems could allow for better therapeutic approaches to the treatments of related diseases. Dopaminergic (DAergic) and cholinergic neurotransmitter system regulate various brain functions that include cognition, movement, emotion, etc. This review focuses on the interaction between the brain DAergic and cholinergic systems with respect to the pathogenesis and treatment of schizophrenia and Parkinson's disease (PD). We first discussed the selection of motor plans at the level of basal ganglia, the major DAergic and cholinergic pathways in the brain, and the receptor subtypes involved in the interaction between the two signaling systems. Next, the roles of each signaling system were discussed in the context of the negative symptoms of schizophrenia, with a focus on the α7 nicotinic cholinergic receptor and the dopamine D receptor in the prefrontal cortex. In addition, the roles of the nicotinic and dopamine receptors were discussed in the context of regulation of striatal cholinergic interneurons, which play crucial roles in the degeneration of nigrostriatal DAergic neurons and the development of L-DOPA-induced dyskinesia in PD patients. Finally, we discussed the general mechanisms of nicotine-induced protection of DAergic neurons.
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http://dx.doi.org/10.3390/ijms22094299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122651PMC
April 2021

β-Arrestin1 and GPCR kinase2 play permissive roles in Src-mediated endocytosis of α4β2 nicotinic ACh receptors.

Br J Pharmacol 2021 Apr 12. Epub 2021 Apr 12.

Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwangju, Republic of Korea.

Background And Purpose: The α4β2 nicotinic ACh receptor (nAChR), a subtype of the ligand-gated ion channel, is abundantly expressed in the brain and is implicated in several neurological disorders. The endocytosis of nAChRs plays important roles in the pathogenesis of neurological diseases, but the underlying molecular mechanisms remain poorly understood.

Experimental Approach: Loss-of-function approaches and mutants of α4β2 nAChRs that display different endocytic properties were used to identify the cellular components and processes responsible for endocytosis. The signalling cascade that leads to endocytosis was deduced via protein interactions in predicted cellular components. The endocytosis of α4β2 nAChRs was determined and crosschecked using an ELISA and radioligand assay.

Key Results: Endocytosis of α4β2 nAChRs occurred through clathrin-mediated endocytosis in a dynamin-dependent manner. 14-3-3η-dependent Src-mediated phosphorylation of the nAChR α4 subunit at Y575 was required for nAChR endocytosis, and this occurred with the assistance of β-arrestin1 and GPCR kinase 2 (GRK2) without the need for kinase activity. Endocytosis triggered the mouse double minute 2 homologue-mediated ubiquitination and subsequent down-regulation of α4β2 nAChRs.

Conclusions And Implications: α4β2 nAChR, an ionophore receptor, employs the metabotropic signalling pathway required for endocytosis, which leads to ubiquitination and down-regulation. Further, GRK2 and β-arrestin1, usually associated with GPCR signalling, are involved in the endocytosis of α4β2 nAChRs via different mechanisms. Considering the functional and pathological implications of nAChR endocytosis, results obtained in this study are crucial for the progression of basic research and clinical investigations.
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http://dx.doi.org/10.1111/bph.15495DOI Listing
April 2021

Review of recent developments in surface nanocrystallization of metallic biomaterials.

Nanoscale 2021 Feb;13(4):2286-2301

Department of Materials Engineering, Indian Institute of Science, Bangalore, 560012 India.

Metallic materials are widely used to prepare implants for both short-term and long-term use in the human body. The performance of these implants is greatly influenced by their surface characteristics, which has motivated the development of several surface modification techniques. Surface severe plastic deformation (S2PD) techniques have emerged as promising strategies to enhance the performance of metallic biomaterials. They do not involve chemical modification of the surface and impart minimal changes to the surface topography. S2PD processes are based on the principle of generating nanocrystals at the surface, which can improve performance metrics, such as fatigue, wear, corrosion resistance, and biocompatibility through various mechanisms, such as surface hardening and alterations to the surface oxide layer. This review presents the state of the art on the development of different S2PD processes and their applications on metallic biomaterials. Brief descriptions of the different processes have been provided, followed by a discussion on the microstructural changes induced by these processes for different generations of biomaterials. The effect of S2PD on surface and bulk characteristics of the biomaterials and their performance is critically reviewed. As an emerging class of surface engineering techniques in biomaterials science, more work is needed to fully leverage their potential in this field, and these opportunities are discussed in this review.
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http://dx.doi.org/10.1039/d0nr07566cDOI Listing
February 2021

A novel molecular mechanism responsible for phosphorylation-independent desensitization of G protein-coupled receptors exemplified by the dopamine D receptor.

Biochem Biophys Res Commun 2020 07 3;528(3):432-439. Epub 2020 Jun 3.

Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwang-Ju, 61186, Republic of Korea. Electronic address:

GRK-mediated receptor phosphorylation followed by association with β-arrestins has been proposed to be the molecular mechanism involved in the desensitization of G protein-coupled receptors (GPCRs). However, this mechanism does not explain the desensitization of some GPCRs, such as dopamine D receptor (DR), which does not undergo GRK-mediated phosphorylation. Loss-of-function approaches and mutants of dopamine D receptor and DR, which exhibit different desensitization properties, were used to identify the cellular components and processes responsible for desensitization. DR mediated the recruitment of Mdm2 to the cytosol, which resulted in the constitutive ubiquitination of β-arrestin2 in the resting state. Under desensitization conditions, cytosolic Mdm2 returned to the nucleus, resulting in the deubiquitination of cytosolic β-arrestins. Deubiquitinated β-arrestins formed a tight complex with Gβγ, thereby sequestering it, causing interference in DR signaling. In conclusion, this study shows that β-arrestins, depending on their ubiquitination status, control the G protein cycling by regulating their interactions with Gβγ. This is a novel mechanism proposed to explain how certain GPCRs can undergo desensitization without receptor phosphorylation.
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http://dx.doi.org/10.1016/j.bbrc.2020.05.197DOI Listing
July 2020

Metabotropic signaling cascade involved in α4β2 nicotinic acetylcholine receptor-mediated PKCβII activation.

Biochim Biophys Acta Mol Cell Res 2020 08 15;1867(8):118721. Epub 2020 Apr 15.

Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwang-Ju 61186, Republic of Korea. Electronic address:

Nicotinic acetylcholine receptors (nAChRs) belong to the ionophore receptor family, which regulates plasma membrane conductance to Na, K, and Ca ions. Some studies, however, have shown that nAChRs also employ second messengers for intracellular signaling. We previously showed that α4β2 nAChR mediates the translocation of protein kinase CβII (PKCβII) from the cytoplasm to the plasma membrane, which is a typical activation marker for PKCβII. In this study, we investigated the molecular mechanisms underlying PKCβII activation through α4β2 nAChR. α4β2 nAChR is the most abundant nAChR subtype and is implicated in various brain functions and diseases. Putative α4β2 nAChR signaling components were identified by knockdown or chemical inhibition of candidate proteins, and the signaling cascade was deduced by protein interactions in predicted cellular components. α4β2 nAChR-mediated PKCβII translocation was found to occur in an ionophore activity-independent manner. Nicotinic stimulation of α4β2 nAChR activated Src in a β-arrestin1 and 14-3-3η-dependent manner. Activated Src phosphorylated the tyrosine residue(s) on Syk molecules, which in turn interacted with phospholipase C γ1 to trigger the translocation of PKCβII to the cell membrane by elevating cellular diacylglycerol levels. The activated PKCβII in turn exerted a positive feedback effect on Src activation, suggesting that α4β2 nAChR signaling is amplified by a positive feedback loop. These findings provide novel information for unveiling the previously unclear metabotropic second messenger-based signal transduction pathway of nAChRs.
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http://dx.doi.org/10.1016/j.bbamcr.2020.118721DOI Listing
August 2020

Surface mechanical attrition treatment of low modulus Ti-Nb-Ta-O alloy for orthopedic applications.

Mater Sci Eng C Mater Biol Appl 2020 May 4;110:110729. Epub 2020 Feb 4.

Department of Materials Engineering, Indian Institute of Science, Bangalore 560012, India. Electronic address:

Surface mechanical attrition treatment (SMAT) is recognized as a surface severe plastic deformation (SPD) method that is effective in improving the surface-dependent mechanical and functional properties of conventional metallic biomaterials. In this study, we aimed to systemically investigate the effect of SMAT on the physical, electrochemical, tribological and biological performances of a newly developed low modulus β Ti-Nb-Ta-O alloy with two different microstructures, namely, single phase β-treated and dual phase β + α aged. The microhardness results showed considerable hardening for the β-treated condition due to formation of deformation substructures; that was associated with increased corrosion resistance resulting from a stronger and denser passive layer on the surface, as revealed by Tafel polarization, impedance studies and Mott-Scottky plots. The wear volume loss during fretting in serum solution was found to decrease by 46% while friction coefficient decreased only marginally, due to presence of a harder and more brittle surface. In the β + α condition of the alloy, minimal hardening was observed due to coarsening of the precipitates during SMAT. However, this also reduced the number of α-β interfaces, which in turn minimized the tendency for galvanic corrosion resulting in lower corrosion rate after SMAT. Wear resistance was enhanced after SMAT, with 32% decrease in wear volume loss and 21% decrease in friction coefficient resulted due to improved ductility on the surface. The attachment and growth of osteoblasts on the alloys in vitro were not affected by SMAT and was comparable to that on commercially pure Ti. Taken together, these results provide new insights into the effects of surface SPD of low modulus β- Ti alloys for orthopedic applications and underscore the importance of the initial microstructure in determining the performance of the alloy.
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http://dx.doi.org/10.1016/j.msec.2020.110729DOI Listing
May 2020

Catalpol and Mannitol, Two Components of , Exhibit Anticonvulsant Effects Probably via GABA Receptor Regulation.

Biomol Ther (Seoul) 2020 Mar;28(2):137-144

Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, Seoul 01795, Republic of Korea.

Epilepsy is a brain disorder that affects millions of people worldwide and is usually managed using currently available antiepileptic drugs, which result in adverse effects and are ineffective in approximately 20-25% of patients. Thus, there is growing interest in the development of new antiepileptic drugs with fewer side effects. In a previous study, we showed that a (RG) water extract has protective effects against electroshock- and pentylenetetrazol (PTZ)-induced seizures, with fewer side effects. In this study, the objective was to identify the RG components that are responsible for its anticonvulsant effects. Initially, a number of RG components (aucubin, acteoside, catalpol, and mannitol) were screened, and the anticonvulsant effects of different doses of catalpol, mannitol, and their combination on electroshock- and chemically (PTZ or strychnine)-induced seizures in mice, were further assessed. Gamma-aminobutyric acid (GABA) receptor binding assay and electroencephalography (EEG) analysis were conducted to identify the potential underlying drug mechanism. Additionally, treated mice were tested using open-field and rotarod tests. Catalpol, mannitol, and their combination increased threshold against electroshock-induced seizures, and decreased the percentage of seizure responses induced by PTZ, a GABA antagonist. GABA receptor binding assay results revealed that catalpol and mannitol are associated with GABA receptor activity, and EEG analysis provided evidence that catalpol and mannitol have anticonvulsant effects against PTZ-induced seizures. In summary, our results indicate that catalpol and mannitol have anticonvulsant properties, and may mediate the protective effects of RG against seizures.
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http://dx.doi.org/10.4062/biomolther.2019.130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059811PMC
March 2020

Mdm2-mediated ubiquitination of PKCβII in the nucleus mediates clathrin-mediated endocytic activity.

Biochem Pharmacol 2019 12 18;170:113675. Epub 2019 Oct 18.

Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwang-Ju 61186, Republic of Korea. Electronic address:

Cellular stimuli that increase diacylglycerol levels activate several protein kinase C (PKC) isoforms; however, prolonged stimulation depletes cells of PKCs. Ubiquitination is a critical cellular event that mediates the degradation of numerous proteins, including PKCs, but little is known of the molecular mechanisms involved in PKC ubiquitination. PKCβII is the most widely expressed PKC isoform and regulates a variety of cellular functions. Here, we show that in response to stimulation of the Gq-coupled angiotensin II type 1 receptor or treatment with phorbol ester, Mdm2, E3 ubiquitin ligase, interacted with PKCβII isotype in the nucleus, resulting in ubiquitination of PKCβII at the C-terminal K668 and K672 residues and its subsequent downregulation. Ubiquitinated PKCβII mediated the clathrin-mediated endocytosis of G protein-coupled receptors like the D and D dopamine receptors; in contrast, non-ubiquitinated PKCβII mediated an as yet uncharacterized clathrin- and caveolar-independent endocytic pathway. In conclusion, we characterized the molecular mechanisms involved in the activity-dependent ubiquitination of PKCβII that determine its life span and endocytic roles. Considering that PKCβII plays an important role in the development of various diseases, including diabetic vasculitis, the results obtained in this study will contribute to better understanding the pathogenesis of PKCβII-related diseases.
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http://dx.doi.org/10.1016/j.bcp.2019.113675DOI Listing
December 2019

Role of aging induced α precipitation on the mechanical and tribocorrosive performance of a β Ti-Nb-Ta-O orthopedic alloy.

Mater Sci Eng C Mater Biol Appl 2019 Oct 24;103:109755. Epub 2019 May 24.

Department of Materials Engineering, Indian Institute of Science, Bangalore 560012, India. Electronic address:

A low modulus β Ti-Nb-Ta-O alloy was subjected to heat treatment to investigate its phase stability upon aging. The resultant effect on the mechanical and functional properties was systematically evaluated. The aging of the β-only microstructure, obtained by solutionizing and quenching, resulted in the formation of ultrafine α-precipitates with increasing order of size as the aging temperature increased from 400 °C to 600 °C. The variation in the size of α-precipitates effected the mechanical properties at the three different aging temperature. The highest hardening observed at 400 °C was associated with macroscopic embrittlement, whereas age softening was observed in samples aged at 600 °C due to coarsening of precipitates and softening of the β-matrix. In contrast, aging at 500 °C resulted in about 32% increase in tensile strength from the β-solutionized condition. As the samples aged at 500 °C showed optimum combination of mechanical properties among the aged samples, these were further characterized for their electrochemical, tribological and biological responses. The fretting wear studies showed that the wear rate of the solution-treated samples increased after aging due to the higher corrosion rate leading to a higher rate of tribocorrosive dissolution and formation of a transfer layer harder than that of solution treated sample. The Ti-Nb-Ta-O alloy supported the attachment and proliferation of osteoblasts similar to that on commercially pure Ti. Taken together, this work provides new insights into the preparation of next-generation Ti alloys for biomedical applications with high strength and low modulus through microstructural control induced by heat treatment.
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http://dx.doi.org/10.1016/j.msec.2019.109755DOI Listing
October 2019

α4β2 nicotinic acetylcholine receptor downregulates D dopamine receptor expression through protein kinase C activation.

Biochem Biophys Res Commun 2019 06 9;514(3):665-671. Epub 2019 May 9.

Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwang-Ju, 61186, Republic of Korea. Electronic address:

Receptor transactivation or crosstalk refers to instances in which the signaling of a given receptor is regulated by different classes of receptors. Functional crosstalk between α4β2 nicotinic acetylcholine receptor (nAChR) and D dopamine receptor (DR) that belong to the family of ligand-gated ion channels and G protein-coupled receptors, respectively, has been reported from brain dopaminergic neurons. For example, DR is involved in the development of reward-related behaviors induced by α4β2 nAChR stimulation. However, the molecular mechanisms involved in their crosstalk remain unclear. Among PKC isoforms (α, βII, γ, and δ) evaluated in this study, PKCβII interacted with DR and potentiated DR endocytosis. Following α4β2 nAChR stimulation, activated PKCβII translocated to the plasma membrane to induce clathrin-mediated endocytosis of DR, resulting in downregulation and signal inhibition. Considering that DR plays important roles in mediating reward-related physiological actions of α4β2 nAChR, this study could provide a new insight into the regulatory mechanism involved in nicotine addiction.
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http://dx.doi.org/10.1016/j.bbrc.2019.05.020DOI Listing
June 2019

The novel methoxetamine analogs N-ethylnorketamine hydrochloride (NENK), 2-MeO-N-ethylketamine hydrochloride (2-MeO-NEK), and 4-MeO-N-ethylketamine hydrochloride (4-MeO-NEK) elicit rapid antidepressant effects via activation of AMPA and 5-HT receptors.

Psychopharmacology (Berl) 2019 Jul 19;236(7):2201-2210. Epub 2019 Mar 19.

Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, 815 Hwarangro, Nowon-gu, Seoul, 01795, Republic of Korea.

Rationale: Depressive syndrome or depression is a debilitating brain disorder affecting numerous people worldwide. Although readily available, current antidepressants have low remission rates and late onset times. Recently, N-methyl--aspartate (NMDA) receptor antagonists, like ketamine and methoxetamine (MXE), were found to elicit rapid antidepressant effects. As the search for glutamatergic-based antidepressants is increasing, we synthesized three novel MXE analogs, N-ethylnorketamine hydrochloride (NENK), 2-MeO-N-ethylketamine hydrochloride (2-MeO-NEK), and 4-MeO-N-ethylketamine hydrochloride (4-MeO-NEK).

Objectives: To determine whether the three novel MXE analogs induce antidepressant effects and explore their mechanistic correlation.

Methods: We examined their affinity for NMDA receptors through a radioligand binding assay. Mice were treated with each drug (2.5, 5, and 10 mg/kg), and their behavior was assessed 30 min later in the forced swimming test (FST), tail suspension test (TST), elevated plus-maze (EPM) test, and open-field test (OFT). Another group of mice were pretreated with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione (NBQX), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, or ketanserin (KS), a 5-HT receptor antagonist, during the FST. We also measured mRNA levels of the AMPA receptor subunits GluA1 and GluA2, brain-derived neurotrophic factor (BDNF), and mammalian target of rapamycin (mTOR) in the hippocampus and prefrontal cortex.

Results: The MXE analogs showed affinity to NMDA receptors and decreased immobility time during the FST and TST. NBQX and KS blocked their effects in the FST. The compounds did not induce behavioral alteration during the EPM and OFT. The compounds altered GluA1, GluA2, and BDNF mRNA levels.

Conclusion: These results suggest that the novel MXE analogs induce antidepressant effects, which is likely via AMPA and 5-HT receptor activation.
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http://dx.doi.org/10.1007/s00213-019-05219-xDOI Listing
July 2019

Design, synthesis, and systematic evaluation of 4-arylpiperazine- and 4-benzylpiperidine napthyl ethers as inhibitors of monoamine neurotransmitters reuptake.

Bioorg Med Chem 2018 11 26;26(20):5538-5546. Epub 2018 Sep 26.

College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea. Electronic address:

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 35 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.
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http://dx.doi.org/10.1016/j.bmc.2018.09.033DOI Listing
November 2018

Triple reuptake inhibitors: Design, synthesis and structure-activity relationship of benzylpiperidine-tetrazoles.

Bioorg Med Chem 2017 10 27;25(20):5278-5289. Epub 2017 Jul 27.

College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea. Electronic address:

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 2q, in particular, showed potent serotonin reuptake inhibition, validating our design approach.
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http://dx.doi.org/10.1016/j.bmc.2017.07.046DOI Listing
October 2017

Design, synthesis and in vitro activity of 1,4-disubstituted piperazines and piperidines as triple reuptake inhibitors.

Bioorg Med Chem 2017 04 27;25(7):2266-2276. Epub 2017 Feb 27.

College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea. Electronic address:

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-1H-tetrazol-1-yl)butyl)-4-(3-phenylpropyl)piperazine (2i), was able to inhibit monoamine neurotransmitter reuptake in an in vitro test (IC=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.
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http://dx.doi.org/10.1016/j.bmc.2017.02.051DOI Listing
April 2017

Molecular Signature That Determines the Acute Tolerance of G Protein-Coupled Receptors.

Biomol Ther (Seoul) 2017 May;25(3):239-248

Pharmacology Laboratory, College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea.

Desensitization and acute tolerance are terms used to describe the attenuation of receptor responsiveness by prolonged or intermittent exposure to an agonist. Unlike desensitization of G protein-coupled receptors (GPCRs), which is commonly explained by steric hindrance caused by the β-arrestins that are translocated to the activated receptors, molecular mechanisms involved in the acute tolerance of GPCRs remain unclear. Our studies with several GPCRs and related mutants showed that the acute tolerance of GPCRs could occur independently of agonist-induced β-arrestin translocation. A series of co-immunoprecipitation experiments revealed a correlation between receptor tolerance and interactions among receptors, β-arrestin2, and Gβγ. Gβγ displayed a stable interaction with receptors and β-arrestin2 in cells expressing GPCRs that were prone to undergo tolerance compared to the GPCRs that were resistant to acute tolerance. Strengthening the interaction between Gβγ and β-arrestin rendered the GPCRs to acquire the tendency of acute tolerance. Overall, stable interaction between the receptor and Gβγ complex is required for the formation of a complex with β-arrestin, and determines the potential of a particular GPCR to undergo acute tolerance. Rather than turning off the signal, β-arrestins seem to contribute on continuous signaling when they are in the context of complex with receptor and Gβγ.
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http://dx.doi.org/10.4062/biomolther.2016.193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5424633PMC
May 2017

Exploration of substituted arylpiperazine-tetrazoles as promising dual norepinephrine and dopamine reuptake inhibitors.

Bioorg Med Chem 2016 11 3;24(21):5546-5555. Epub 2016 Sep 3.

College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea. Electronic address:

In the search for potent dual norepinephrine and dopamine reuptake inhibitors, several substituted arylpiperazine-tetrazoles were designed, synthesized and evaluated for their neurotransmitter reuptake inhibitory activities. Various derivatives exhibited selective and strong neurotransmitter reuptake inhibitory activity. In particular, compounds with a three-carbon linker displayed selective and stronger potency than those with two-carbon and four-carbon linkers. Interestingly, six compounds, 9b, 9c, 9d, 9o, 9q and 9u displayed more effective activity than the standard drug, bupropion. The provided SAR data and potent biological activity can offer useful guidelines for designing dual norepinephrine and dopamine reuptake inhibitors as effective therapeutic agents for treatment of several central nervous system diseases.
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http://dx.doi.org/10.1016/j.bmc.2016.09.005DOI Listing
November 2016

Design, synthesis, and biological evaluation of arylpiperazine-benzylpiperidines with dual serotonin and norepinephrine reuptake inhibitory activities.

Bioorg Med Chem 2016 May 28;24(9):2137-45. Epub 2016 Mar 28.

College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea. Electronic address:

The limitations of established serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake inhibitors necessitate the development of safer and more effective therapeutic agents. Based on the structures of 4-benzylpiperidine carboxamides and trazodone, arylpiperazine-benzylpiperidines with chemical scaffolds different from those of marketed drugs were designed, synthesized, and evaluated for their neurotransmitter reuptake inhibitory activities. The majority of the synthesized compounds showed greater NE than 5-HT reuptake inhibition. The activities were even greater than those of the standard drug, venlafaxine hydrochloride were. The derivatives with a three-carbon linker showed better activities than the derivatives with a two-carbon linker. Among the newly synthesized compounds, 2d exhibited the strongest reuptake inhibition of the neurotransmitters (IC50=0.38 μM for NE and 1.18 μM for 5-HT). The biological activity data demonstrate that arylpiperazine-benzylpiperidines have the potential to be developed as a new class of therapeutic agents to treat neuropsychiatric and neurodegenerative disorders.
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http://dx.doi.org/10.1016/j.bmc.2016.03.044DOI Listing
May 2016

Design, synthesis and evaluation of bitopic arylpiperazinephenyl-1,2,4-oxadiazoles as preferential dopamine D3 receptor ligands.

Bioorg Med Chem 2016 Jan 2;24(2):191-200. Epub 2015 Dec 2.

College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea. Electronic address:

The dopamine D3 receptor (D3R) was proposed as a therapeutic target for drug development to treat drug abuse and addiction and neuropsychiatric disorders. Several D3R-selective modulators over the dopamine D2 receptor (D2R) can avoid extrapyramidal symptoms (EPS) and hyperprolactinemia. However, few biased D3R ligands were identified or showed a narrow range of selectivity at the D3R over D2R because of their high sequence homology. Herein, we designed, synthesized and evaluated the binding affinity of a series of bitopic ligands: arypiperazine-phenyl-1,2,4-oxadiazoles. Compound 9e·HCl was the most potent and selective D3R modulator among these bitopic ligands. Molecular modeling revealed that D3R selectivity depends on the divergence of secondary binding pocket (SBP) in D3R and D2R. Specifically, non-conserved Tyr36, EL1 especially non-conserved Thr92 and Gly94, and EL2 Val180, Cys181 and Ser182 of D3R may contribute to D3R specificity over D2R.
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http://dx.doi.org/10.1016/j.bmc.2015.12.002DOI Listing
January 2016