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A highly selective fluorescent probe for real-time imaging of UDP-glucuronosyltransferase 1A8 in living cells and tissues

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Frontiers of Chemical Science and Engineering 2022年第1期16卷 103-111页

作者： Mingyue Zhu Zhenhao Tian Lingling Jin Xiaokui Huo Chao Wang Jingnan Cui Yan Tian Xiangge Tian Lei Feng College of Pharmacy School of MedicineKey Laboratory of Elemene Class Anti-Cancer Chinese MedicinesEngineering Laboratory of Development and Application of Traditional Chinese MedicinesHangzhou Normal UniversityHangzhou 311121China Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention College of PharmacyCollege of Integrative MedicineDalian Medical UniversityDalian 116044China School of Life Sciences Northwestern Polytechnical UniversityXi’an 710072China State Key Laboratory of Fine Chemicals Dalian University of TechnologyDalian 116024China

Uridine diphosphate(UDP)-glucuronosyltransferases(UGTs)are enzymes involved in the biotransformation of important endogenous compounds such as steroids,bile acids,and hormones as well as exogenous substances including drugs,environmental toxicants,and ***,a novel fluorescent probe BDMP was developed based on boron-dipyrromethene(BODIPY)with high sensitivity for the detection of *** glucuronidation of BDMP not only exhibited a redemission wavelength(lex/lem=500/580 nm),but also displayed an excellent UGT1A8-dependent fluorescence signal with a good linear relationship with UGT1A8 *** on this perfect biocompatibility and cell permeability,BDMP was successfully used to image endogenous UGT1A8 in human cancer cell lines(LoVo and HCT15)in real *** addition,BDMP could also be used to visualize UGT1A8 in tumor *** results suggested that BDMP is a promising molecular tool for the investigation of UGT1A8-mediated physiological function in humans.

关键词： UDP-glucuronosyltransferase 1A8 fluorescent probe subtype selectivity fluorescence imaging

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Discovery of an enantiopure N-[2-hydroxy-3-phenyl piperazine propyl]-aromatic carboxamide derivative as highly selectiveα_(1D/1A)-adrenoceptor antagonist and homology modelling

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Chinese Chemical Letters 2024年第11期35卷 435-441页

作者： Junjun Huang Ran Chen Yajian Huang Hang Zhang Anran Zheng Qing Xiao Dan Wu Ruxia Duan Zhi Zhou Fei He Wei Yi The Fifth Affiliated Hospital Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target&Clinical Pharmacologythe NMPA and State Key Laboratory of Respiratory DiseaseSchool of Pharmaceutical SciencesGuangzhou Medical UniversityGuangzhou 511436China Department of Pharmacy The Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510150China School of Traditional Chinese Medicine Southern Medical UniversityGuangzhou 510515China

α_(1)-Adrenergic receptor(AR)blockers can be effective for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms(BPH/LUTS),their usage is limited by cardiovascular-related side effects that are caused by the subtype nonselective nature or low selectivity of many current *** previously reported that phenylpiperazine analogues with amide and propane linker were moderateα_(1D/1A)adrenoceptor antagonists and exhibited better anti-BPH effect than lead compound naftopidil(NAF)in vivo,however,with modestα_(1D/1A)-subtype ***,we replaced propane moiety with2-hydroxypropanol linker and synthesized twenty-seven racemic derivatives with modified aromatic and hetero aromatic *** these new compounds,quinoline surrogate 17 exhibited extremely weak antagonistic affinity onα_(1B)in both cell-based calcium assay and tissue-based functional assay,so that elicited significantα_(1A/1B)andα_(1D/1B)***,the R enantiomer of 17 preferentially displayed superior anti-BPH effect in rat model compared with S-17,supporting ligand regulates the receptor in a highly stereospecific ***,the computer-aided modelling research was also performed in order to deeply understand the unique binding mode of R-17 in complex withα_(1A)and the subtype receptor selectivity for R-17 was also rationalized in this *** together,our work enriched the diversity of phenylpiperazines for the treatment of BPH/LUTS,and provided a basis for discovery ofα_(1D/1A)-selective ligands.

关键词： Benign prostatic hyperplasia α_(1)-AR antagonist Phenylpiperazine Homology modelling subtype selectivity

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Identification and optimization of a potent and highly selective D3 dopamine receptor agonist

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中国药理学与毒理学杂志 2017年第10期31卷 950-951页

作者： Amy E MORITZ R Benjamin FREE Warren WEINER Muzna BACHANI Trevor DOYLE Noel SOUTHALL Marc FERRER Jonathan A JAVITCH Joseph STEINER Ara ABRAMYAN Lei SHI Jeffrey AUBé Kevin FRANKOWSKI David R SIBLEY Molecular Neuropharmacology Section National Institute of Neurological Disorders and StrokeNational Institutes of Health Bethesda MD 20814 University of North Carolina Chapel Hill NC27599 Neurotherapeutic Development Unit National Institute of Neurological Disorders and StrokeNational Institutes of Health Bethesda MD 20814 National Center for Advancing Translational Sciences Rockville MD 20892 Columbia University New York NY 10032 Computational Chemistry and Molecular Biophysics Unit Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse National Institutes of Health Baltimore MD 21224

OBJECTIVE Dopamine receptors(DRs) are involved in the development and treatment of many neuropsychiatric *** available dopaminergic drugs modulate both DRD2 and DRD3,leading to side effects and uncertainty as to the roles each DR subtype plays *** lab employed high throughput screening paradigms to discover highly selective modulators for the *** The NIH Molecular Libraries Program 400,000 + small molecule library was screened using the Discove Rx Path Hunter?β-arrestin assay for compounds that activate the DRD3 without effects on the *** and counter-screens assessed selectivity and mechanisms of *** identified 62 potential agonists,and chose the most promising to perform a structure-activity relationship(SAR) study to increase potency while maintaining *** lead compound identified through this process,ML417,was also characterized using bioluminescence resonance energy transfer(BRET)-based β-arrestin recruitment and G-protein activation assays as well as p-ERK *** neuroprotective properties of this compound were assessed using a SHSY5 Y neuronal cell *** ML417 displays potent,DRD3-selective agonist activity in multiple functional *** and functional GPCR screens(>165 receptors) show ML417 has limited cross-reactivity with other ***417 also displays superior(compared to the reference compound pramipexole),dose-dependent protection against a decrease in neurite length induced by 10 μmol·L^(-1) of the neurotoxin,6-hydroxydopamine,in the SHSY5 Y cell *** We have discovered and characterized ML417,a potent and highly selective DRD3 *** compound will be useful as a research tool,and may prove useful as a therapeutic drug lead.

关键词： Dopamine receptor high throughput screening subtype selectivity neuroprotection

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