CN102277154B - Phenyl piperazine small-molecule fluorescent probe of alpha1-adrenergic receptor and application thereof - Google Patents
Phenyl piperazine small-molecule fluorescent probe of alpha1-adrenergic receptor and application thereof Download PDFInfo
- Publication number
- CN102277154B CN102277154B CN2011101010825A CN201110101082A CN102277154B CN 102277154 B CN102277154 B CN 102277154B CN 2011101010825 A CN2011101010825 A CN 2011101010825A CN 201110101082 A CN201110101082 A CN 201110101082A CN 102277154 B CN102277154 B CN 102277154B
- Authority
- CN
- China
- Prior art keywords
- adrenergic receptor
- fluorescent probe
- application
- preparation
- alpha1
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000007850 fluorescent dye Substances 0.000 title claims abstract description 20
- -1 Phenyl piperazine small-molecule Chemical class 0.000 title abstract description 7
- 102000030619 alpha-1 Adrenergic Receptor Human genes 0.000 title abstract description 3
- 108020004102 alpha-1 Adrenergic Receptor Proteins 0.000 title abstract description 3
- 238000002360 preparation method Methods 0.000 claims abstract description 20
- 150000003384 small molecules Chemical class 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical class C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 claims description 5
- 101001026137 Cavia porcellus Glutathione S-transferase A Proteins 0.000 claims description 4
- 101001026109 Gallus gallus Glutathione S-transferase Proteins 0.000 claims description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N aminothiocarboxamide Natural products NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 8
- 230000000144 pharmacologic effect Effects 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 229910052736 halogen Inorganic materials 0.000 abstract description 2
- 150000002367 halogens Chemical class 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
- 102000004305 alpha Adrenergic Receptors Human genes 0.000 abstract 2
- 108090000861 alpha Adrenergic Receptors Proteins 0.000 abstract 2
- 239000002994 raw material Substances 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- 238000011282 treatment Methods 0.000 abstract 1
- 102000005962 receptors Human genes 0.000 description 26
- 108020003175 receptors Proteins 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 238000001556 precipitation Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000011160 research Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000000523 sample Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 4
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 4
- 229960004756 ethanol Drugs 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- IUNJCFABHJZSKB-UHFFFAOYSA-N 2,4-dihydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C(O)=C1 IUNJCFABHJZSKB-UHFFFAOYSA-N 0.000 description 2
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical class CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 108091006027 G proteins Proteins 0.000 description 2
- 102000030782 GTP binding Human genes 0.000 description 2
- 108091000058 GTP-Binding Proteins 0.000 description 2
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 2
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical class CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 description 2
- 206010031127 Orthostatic hypotension Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000674 adrenergic antagonist Substances 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000003809 water extraction Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- VNZLQLYBRIOLFZ-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazine Chemical compound COC1=CC=CC=C1N1CCNCC1 VNZLQLYBRIOLFZ-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 239000002028 Biomass Substances 0.000 description 1
- RUUZUNGEVFHYQZ-UHFFFAOYSA-N COc1cc(N2CCN(CCN)CC2)ccc1 Chemical compound COc1cc(N2CCN(CCN)CC2)ccc1 RUUZUNGEVFHYQZ-UHFFFAOYSA-N 0.000 description 1
- FCSPNTWFYRQKDS-UHFFFAOYSA-N COc1ccccc1N1CCN(CCNC(Nc(cc2)cc(C(O)=O)c2C(c(c(O2)c3)ccc3O)=C(C=C3)C2=CC3=O)=S)CC1 Chemical compound COc1ccccc1N1CCN(CCNC(Nc(cc2)cc(C(O)=O)c2C(c(c(O2)c3)ccc3O)=C(C=C3)C2=CC3=O)=S)CC1 FCSPNTWFYRQKDS-UHFFFAOYSA-N 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 208000001089 Multiple system atrophy Diseases 0.000 description 1
- 206010028748 Nasal obstruction Diseases 0.000 description 1
- IRZWHILMNSFEAF-UHFFFAOYSA-N OC(c(cc(cc1)N=C=S)c1C(c(c(O1)c2)ccc2O)=C(C=C2)C1=CC2=O)=O Chemical compound OC(c(cc(cc1)N=C=S)c1C(c(c(O1)c2)ccc2O)=C(C=C2)C1=CC2=O)=O IRZWHILMNSFEAF-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 239000000951 adrenergic alpha-1 receptor antagonist Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000011953 bioanalysis Methods 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical class O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 238000005558 fluorometry Methods 0.000 description 1
- 239000005090 green fluorescent protein Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 229960001999 phentolamine Drugs 0.000 description 1
- MRBDMNSDAVCSSF-UHFFFAOYSA-N phentolamine Chemical compound C1=CC(C)=CC=C1N(C=1C=C(O)C=CC=1)CC1=NCCN1 MRBDMNSDAVCSSF-UHFFFAOYSA-N 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-N propynoic acid Chemical compound OC(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 229910052761 rare earth metal Inorganic materials 0.000 description 1
- 150000002910 rare earth metals Chemical class 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 230000004960 subcellular localization Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B57/00—Other synthetic dyes of known constitution
- C09B57/02—Coumarine dyes
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B11/00—Diaryl- or thriarylmethane dyes
- C09B11/04—Diaryl- or thriarylmethane dyes derived from triarylmethanes, i.e. central C-atom is substituted by amino, cyano, alkyl
- C09B11/06—Hydroxy derivatives of triarylmethanes in which at least one OH group is bound to an aryl nucleus and their ethers or esters
- C09B11/08—Phthaleins; Phenolphthaleins; Fluorescein
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/582—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with fluorescent label
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
- G01N33/9406—Neurotransmitters
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
- G01N2333/72—Assays involving receptors, cell surface antigens or cell surface determinants for hormones
- G01N2333/726—G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Biomedical Technology (AREA)
- Immunology (AREA)
- Food Science & Technology (AREA)
- General Health & Medical Sciences (AREA)
- Microbiology (AREA)
- Organic Chemistry (AREA)
- Pathology (AREA)
- Biotechnology (AREA)
- Medicinal Chemistry (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- Cell Biology (AREA)
- General Physics & Mathematics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a phenyl piperazine small-molecule fluorescent probe of an alpha1-adrenergic receptor and application thereof. General formulas of the small-molecule fluorescent probe are shown as a formula (I) and a formula (II) respectively, wherein R1 represents a single substituent or a multi-substituent of hydroxy, methyl, amino and halogen, and R2 and R3 represent various fluorophores. The fluorescent probe molecule can be used for marking the alpha-adrenergic receptor and be used as a tool drug for researching pharmacological and physiological characteristics of the alpha-adrenergic receptor. In addition, the preparation method of the compound has mild reaction conditions, cheap and easily available raw materials, and simple operations and post-treatments.
Description
Technical field
The present invention relates to the phenylpiperazine analog derivative and as α
1The small molecules fluorescent probe of-adrenergic receptor and the application in the anti-prostate cancer medicine of preparation belong to technical field of pharmaceuticals.
Background technology
α
1-adrenergic receptor is the important member in the G-protein linked receptor family, comprises three kinds of hypotype: α at present
1A, α
1BAnd α
1D[Zhong, H.; Minneman, K.P.Alphal-adrenoceptor subtypes.Eur J Pharmacol 1999,375,261-276].α
1-adrenergic receptor is found in the disease-related cells such as human benign prostatic hyperplasia and prostate cancer and has [Shi, T. in a large number; Gaivin, R.J.; McC une, D.F.; Gupta, M.; Perez, D.M.Dominance of thealphal-adrenergic receptor and its sub cellular localization in human and TRAMP prostate cancercell lines.J.Recept.Signal Transduct.Res.2007,27,27-45].Studies show that α
1A-adrenergic receptor can mediate down urethra and prostatic contraction, and α
1A-adrenergic receptor selective antagonist can effectively be blocked the prostate gland smooth muscle contraction of agonist induction, and blood pressure is not made significant difference; In addition, lack α
1AThe selectivity of-adrenergic receptor can cause some cardiovascular side effects, such as: orthostatic hypotension (postural hypotension), dizziness, weakness and nasal obstruction etc.In human detrusor urinae of bladder, α
1D-adrenergic receptor mRNA is at α
1Occupy an leading position in the expression of each hypotype of-adrenergic receptor.In addition, also there are some researches show, flow out in the rat model that blocks selectivity α at bladder
1D-adrenergic receptor blocker can suppress non-random smooth muscle of bladder and shrink, thereby alleviates BPH symptom [Docherty, J.R.Subtypes offunctional alphal-adrenoceptor.Cell Mol.Life Sci.2010,67,405-417].Therefore, α
1-adrenergic receptor antagonist is usually used in alleviating relevant the blocking symptom and treat hypertension of benign prostatic hyperplasia (BPH) clinically.
Be accompanied by the development of fluorometry in biological chemistry, medical science and chemical research in recent years, a large amount of fluorescent probes is widely used in [Terai, T. in the various bioanalysiss because of its highly sensitive, dynamic resolution and with the compatibility of biomass cells and physiologic analyses; Nagano, T.Fluorescent probes for bioimaging applications.Curr.Opin.Chem.Biol.2008,12,515-521].At present the kind of fluorescent probe mainly includes machine small molecules, nano-quantum point, rare earth compounding, protein-based etc., wherein the small molecules fluorescent probe have fast, sensitive, high-throughput and easy characteristics such as automatization, be widely used in during the biology of important biomolecule molecules such as protein, nucleic acid and pharmacology detects, the development in fields such as disease mechanisms discussion, clinical diagnosis and drug screening has been had great importance.The small molecules fluorescent probe generally is made up of two portions: pharmacophoric group part (pharmacophore) and fluorophor part (fluorophore).Pharmacophoric group can be combined with the target biological molecules high-affinity with the interaction of part by acceptor, but and fluorophor fluorescence excitation character with labelled protein.The small molecules fluorescent probe research that acts on the G-protein linked receptor has at present become emerging direction and research focus [(a) Kuder, the K. of receptor chemistry field of biology; Kiec-Kononowicz, K.Fluorescent GPCR ligands as new tools in pharmacology.Curr.Med.Chem.2008,15,2132-2143; (b) Leopoldo, M.; Lacivita, E.; Berardi, F.; Perrone, R.Developments in fluorescent probes for receptor research.Drug Discov.Today 2009,14,706-712; (c) Cairo, C.W.; Key, J.A.; Sadek, C.M.Fluorescent small-molecule probes of biochemistry at theplasma membrane.Curr.Opin.Chem.Biol.2010,14,57-63].
Yet, for α
1-adrenergic receptor does not also have fluorescent small molecule probe report, the macromole probe [(a) Awaji, the T. that only have the several pieces of functional green fluorescent proteins of The thesis (GFP) to merge at present; Hirasawa, A.; Kataoka, M.; Shinoura, H.; Nakayama, Y.; Sugawara, T.; Izumi, S.; Tsujimoto, G.Real-time optical monitoringof ligand-mediated internalization of alphalb-adrenoceptor with green fluorescent protein.Mol.Endocrinol.1998,12,1099-1111; (b) Chalothorn, D.; McCune, D.F.; Edelmann, S.E.; Garcia-Cazarin, M.L.; Tsujimoto, G.; Piascik, M.T.Differences in the cellular localizationand agonist-mediatedinternalization properties of the alpha (1)-adrenoceptor subtypes.Mol.Pharmacol.2002,61,1008-1016].This makes and adopts the fluorescent small molecule probe to α
1The biology of-adrenergic receptor and pharmacological property researchdevelopment lag behind.Therefore, if can choose α
1-adrenergic receptor has the part small molecules of high-affinity to be connected with fluorophor as pharmacophoric group, thereby obtains α
1-adrenergic receptor fluorescent probe molecule, and remove to study α with this probe molecule as the instrument medicine
1The pharmacology of-adrenergic receptor and physiologic character certainly will can promote α
1The researchdevelopment of-adrenergic receptor.On the other hand, for α
1The test of-adrenergic receptor and ligand molecular avidity is at present also based on the radio-labeled experiment, this environmental pollution and researchist are healthy and safe all to be a difficult problem, if we can find a desirable alpha 1 adrenergic receptor probe molecule as being at war with property of fluorogenic substrate pharmacological evaluation, also can be α
1The activity research of-adrenergic receptor antagonist or agonist provides a quick pharmacological screening platform.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of phenylpiperazine class α is provided
1Small molecules fluorescent probe of-adrenergic receptor and preparation method thereof, optical activity, biological activity and the application in pharmacy.
For achieving the above object, the present invention adopts following technical proposals:
A kind of phenylpiperazine class α
1The small molecules fluorescent probe of-adrenergic receptor has following general structural formula (I) or (II):
In the formula: R
1For the single of hydroxyl, methyl, amino, halogen or methoxyl group replaces or multi-substituent; R
2, R
3Be various fluorophores.
Preferably, R in the formula
1Be the ortho position methoxyl group earlier; R
2For containing the coumarin kind compound of carboxyl, R
3Be the fluorescein isothiocyanate compounds.
Preferably, be following compound:
N-{2-[4-(2-p-methoxy-phenyl)-1-piperazinyl] ethyl }-7-hydroxyl-1,2-benzopyrone-3-methane amide (b1),
1-(7-hydroxyl-3-1,2-chromene ketone group)-N-{2-[4-(2-p-methoxy-phenyl)-1-piperazinyl] ethyl }-1H-1,2,3-triazole-4-methane amide (b2),
2-(6-hydroxyl-3-oxo-3H-xanthene-9-yl)-5-{3-{2-[4-(2-p-methoxy-phenyl)-1-piperazinyl] ethyl } thiocarbamide } phenylformic acid (b3).
Compound of the present invention is as α
1The application of the small molecules fluorescent probe of-adrenergic receptor.
The application of compound of the present invention in the anti-prostate cancer medicine of preparation.
Compound of the present invention is as instrument medicine research α
1The pharmacology of-adrenergic receptor, physiologic character and application how to regulate and control prostate cancer cell apoptosis signal transduction path.
Compound of the present invention is at α
1Application in-adrenergic receptor antagonist or the agonist activity research.
Embodiment
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
Example one: N-{2-[4-(2-p-methoxy-phenyl)-1-piperazinyl] ethyl }-7-hydroxyl-1, the preparation of 2-benzopyrone-3-methane amide (b1)
The preparation of intermediate a1-2:
The preparation of intermediate (a1-1):
The 100mL flask adds 2.76g 2,4-Dihydroxy benzaldehyde and 25mL dehydrated alcohol, stirring makes the solution becomes clarification, adds the 3.84g diethyl malonate again, in the time of stirring, 0.17g morpholine and 66mg acetic acid are dissolved in the 10mL dehydrated alcohol, then it are added above-mentioned reaction solution, reflux and stir 9h, ice bath cooling reaction solution, separate out a large amount of precipitations, filter drying, get yellow needle-like solid 2.37g, productive rate is 50.64%.
The preparation of intermediate (a1-2):
The 100mL flask drops into 2.37g a1-1, adds the NaOH of 40mL 2M, stirring at room 14h, and the HCl that adds 2M shows acid to solution, separates out a large amount of precipitations, filters, and drying gets yellow solid 1.85g, and productive rate is 90%.
The preparation of intermediate b
The preparation of intermediate 1-b:
The 25mL flask adds 1.47g phthalic imidine, 2.76g salt of wormwood, 2.6mL glycol dibromide and 7mL DMF, stirred overnight at room temperature screws out solvent, with ethyl acetate and water extraction, which floor collection has, and uses saturated ammonium chloride, the saturated sodium-chloride washing, anhydrous magnesium sulfate drying, be threaded to driedly to the greatest extent, recrystallization is separated out a large amount of needle-like white solids, the dry about 1.9g in back, productive rate is 75%.
The preparation of intermediate 2-b:
The 50mL flask adds 0.5g 1-(2-methoxyphenyl) piperazine, 0.51g 1-b, 1.4mLTEA and 20mL acetonitrile, refluxes and stirs 12h, screw out solvent, add the saturated ethanolic soln of hydrogenchloride, collecting precipitation, recrystallization gets pink needle-like crystal 0.6g, and productive rate is 82%.
The preparation of intermediate b:
The 250mL flask adds 2.19g 2-b, 1.46mL hydrazine hydrate and 120mL ethanol, refluxes and stirs 3.5h, is down to room temperature, separate out a large amount of white precipitates, filter, with cold ethanol and ether washing, collect filtrate, add the alkalization of 2M NaOH solution, be spin-dried for, water and ethyl acetate extraction collect which floor is arranged, drying screws out solvent, is oily matter, add the saturated ethanolic soln of HCl, separate out a large amount of precipitations, filter, drying gets pale solid 1.63g, and productive rate is 100%.
1HNMR(600MHz，DMSO-d
6)δppm：8.62(s，3H)，6.91-7.06(m，4H)，3.80(s，3H)，3.66(d，2H)，3.51(d，2H)，3.47(t，2H)，3.36-3.37(m，2H)，3.28(t，2H)，3.15(t，2H)。
The preparation of b1:
The 250mL flask, add 0.41 ga1-2,896 μ L N-methylmorpholines and 70mL methylene dichloride, stirred 30 minutes, 298 μ L isobutyl chlorocarbonates are dissolved in the 15mL methylene dichloride, and cryosel is bathed down and is slowly splashed into, after 40 minutes, 0.43gb and 2.29mL TEA are dissolved in the 25mL methylene dichloride, slowly splash into, rise to stirred overnight at room temperature, steam reaction solution, add the saturated ethanolic soln of HCl, separate out a large amount of precipitations, filter drying, column chromatography purification (sherwood oil: ethyl acetate=1: 3), get target compound 170mg, productive rate is 23.1%, mp:250-250.6 ℃.
1HNMR(600MHz，DMSO-d
6)δppm：11.22(s，1H)，10.06(s，1H)，8.93-8.95(m，1H)，8.83(s，1H)，7.85(d，1H)6.98-7.04(m，2H)，6.89-6.95(m，3H)，6.85(d，1H)，3.79(s，3H)，3.76(q，2H)，3.66(d，2H)，3.50(d，2H)，3.37(q，2H)，3.24(q，2H)，2.99(t，2H)；
13CNMR(300MHz，DMSO-d
6)δppm：164.0，162.4，160.7，156.3，151.8，148.3，139.3，132.0，123.5，120.8，118.3，114.4，113.4，111.9，110.9，101.8，55.3，54.8，51.4(2C)，46.8(2C)，33.9；ESI-MS：m/z424.5[M+H]
+；
μIR(KBr，cm
-1)：3299，1705
Example two: 1-(7-hydroxyl-3-1,2-chromene ketone group)-N-{2-[4-(2-p-methoxy-phenyl)-1-piperazinyl] ethyl }-1H-1, the preparation of 2,3-triazole-4-methane amide (b2)
The synthetic route of b2:
The preparation of intermediate a2-1:
The 250mL flask adds 2.76g 2, and 4-Dihydroxy benzaldehyde, 2.34g acetylaminoacetic acid, 4.92g sodium acetate, anhydrous and 85mL aceticanhydride reflux and stir 5h, in reaction solution impouring frozen water, separate out a large amount of precipitations, filter, drying gets yellow solid 2.03g, and productive rate is 38.9%.
The preparation of intermediate a2-2:
The 250mL flask drops into 0.3 g a2-1, adds 10mL concentrated hydrochloric acid and 5mL ethanol, refluxes and stirs 1h, and is cold slightly, adds frozen water in reaction solution, and ice bath cooling reaction solution slowly adds 0.24gNaNO
2, to stir after 10-15 minute, gradation adds 0.34gNaN
3, behind the stirring 1h, filter, water washing and precipitating, drying gets brown solid 0.2g, and (sherwood oil: ethyl acetate=10: 1) get pure product 0.12g, productive rate is 52.2% to cross post.
The preparation of intermediate a2-3:
0.12g a2-2 is dissolved in 2mL ethanol and the 2mL water, adds 0.13g propynoic acid, 0.11g sodium ascorbate, 120 μ L 0.5M CuSO4 successively, stirring at room 40h in the dark filters, collecting precipitation, and drying gets taupe brown solid 0.1g, and productive rate is 62.5%.
The preparation of b2:
The 250mL flask, add 0.4g a2-3,491 μ L N-methylmorpholines and 60mL methylene dichloride, stirred 30 minutes, 198 μ L isobutyl chlorocarbonates are dissolved in the 15mL methylene dichloride, and cryosel is bathed down and is slowly splashed into, after 40 minutes, 0.44gb and 2.3mL TEA are dissolved in the 35mL methylene dichloride, slowly splash into, rise to stirred overnight at room temperature, steam reaction solution, add the saturated ethanolic soln of HCl, separate out a large amount of precipitations, filter drying, with first alcohol and water recrystallization, get target compound 110mg, productive rate is 14.3%, dec:240 ℃.
1HNMR(600MHz，DMSO-d
6)δppm：11.04(s，1H)，9.83(s，1H)，9.05-9.07(m，1H)，8.97(s，1H)，7.79(s，1H)7.78(d，1H)，6.89-7.04(m，6H)，3.80(s，3H)，3.70-3.73(m，4H)，3.52-3.55(d，2H)，3.40-3.41(m，2H)，3.24-3.27(m，2H)，2.96-3.00(t，2H)；
13CNMR(300MHz，DMSO-d
6)δppm：162.9，159.7，156.3，154.8，151.8，142.3，139.4，137.2，131.1，127.4，123.4，120.8，118.8，118.3，114.4，111.9，110.1，102.2，55.4，55.0，51.5(2C)，46.8(2C)，33.5；
ESI-MS：m/z491.5[M+H]
+；
IR(KBr，cm
-1)：3295，1723
3392(Ar-OH)
Example three: 2-(6-hydroxyl-3-oxo-3H-xanthene-9-yl)-5-{3-{2-[4-(2-p-methoxy-phenyl)-1-piperazinyl] ethyl } thiocarbamide } preparation of phenylformic acid (b3)
The synthetic route of b3:
The 50mL flask adds 136mg b, 1.4mL TEA and 15mL methylene dichloride, stirs and makes its dissolving, under the condition of ice bath, 97mgFITC is dissolved among the 4mL DMF, slowly splashes into, rise to room temperature, stirred 3 days in the dark, screw out solvent, be oily matter, add ethyl acetate and methyl alcohol, separate out a large amount of precipitations, filter, collecting precipitation, with 2M NaOH dissolving, elimination insolubles, add 2MHCl and show acid to solution, separate out a large amount of solids, filter, drying gets tawny solid 80mg, productive rate is 52.3%, mp:188-190 ℃.
1HNMR(600MHz，DMSO-d
6)δppm：10.21(s，2H)，8.28(s，1H)，8.03(s，1H)，7.76(s，1H)，7.17(d，1H)，6.93-6.95(m，2H)，6.85-6.91(m，2H)，6.60-6.67(m，2H)，6.55-6.59(m，4H)，3.77(s，3H)，3.70(s，3H)，3.01(s，4H)，2.65(s，5H)；ESI-MS：m/z?625.4[M+H]
+；
IR(K?Br，cm
-1)：3232，1607(COOH)，3061(Ar-OH)
Optical activity is measured:
Annotate: above all optical properties are all measured in the phosphoric acid buffer of PH=7.4.
Biological activity determination:
Radioligand method detection compound is to α
1Three kinds of hypotype (α of-adrenergic receptor
1A, α
1B and α
1D) avidity:
Annotate: the positive drug phentolamine is to α
1A, α
1BAnd α
1DK
iAnd IC
50Be respectively 0.6,4.8,7.6 and 1.1,10.8,12.5.
Claims (3)
1. phenylpiperazine class α
1The small molecules fluorescent probe of-adrenergic receptor is characterized in that, is one of following compound:
The N-{2-[4-(2-p-methoxy-phenyl)-and the 1-piperazinyl] ethyl }-7-hydroxyl-1,2-benzopyrone-3-methane amide;
1-(7-hydroxyl-3-1,2-chromene ketone group)-the N-{2-[4-(2-p-methoxy-phenyl)-the 1-piperazinyl] ethyl }-1H-1,2,3-triazole-4-methane amide;
2-(6-hydroxyl-3-oxo-3H-xanthene-9-yl)-5-{3-{2-[4-(2-p-methoxy-phenyl)-and the 1-piperazinyl] ethyl } thiocarbamide } phenylformic acid.
2. compound as claimed in claim 1 is as α
1The application of the small molecules fluorescent probe of-adrenergic receptor.
3. the application of compound as claimed in claim 1 in the anti-prostate cancer medicine of preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101010825A CN102277154B (en) | 2011-04-21 | 2011-04-21 | Phenyl piperazine small-molecule fluorescent probe of alpha1-adrenergic receptor and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101010825A CN102277154B (en) | 2011-04-21 | 2011-04-21 | Phenyl piperazine small-molecule fluorescent probe of alpha1-adrenergic receptor and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102277154A CN102277154A (en) | 2011-12-14 |
| CN102277154B true CN102277154B (en) | 2013-08-07 |
Family
ID=45102896
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011101010825A Expired - Fee Related CN102277154B (en) | 2011-04-21 | 2011-04-21 | Phenyl piperazine small-molecule fluorescent probe of alpha1-adrenergic receptor and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102277154B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106810526A (en) * | 2015-11-27 | 2017-06-09 | 南京理工大学 | A kind of vitamin D of cumarin modification2Derivative and its preparation method and application |
| CN108659099B (en) * | 2018-05-21 | 2021-02-02 | 浙江大学 | Mass spectrum probe for detecting activity of angiotensin converting enzyme and application thereof |
| CN109293673A (en) * | 2018-10-10 | 2019-02-01 | 中国药科大学 | A kind of prolyl hydroxylase small-molecule fluorescent probe and preparation method thereof |
| CN115947720B (en) * | 2022-12-07 | 2024-03-29 | 南京师范大学 | Design, preparation and application of beta 3 adrenergic receptor anchoring probe |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1850820A (en) * | 2006-05-18 | 2006-10-25 | 中国药科大学 | Coumarin derivatives, and their preparing method and use as alpha, receptor agonist |
-
2011
- 2011-04-21 CN CN2011101010825A patent/CN102277154B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1850820A (en) * | 2006-05-18 | 2006-10-25 | 中国药科大学 | Coumarin derivatives, and their preparing method and use as alpha, receptor agonist |
Non-Patent Citations (2)
| Title |
|---|
| 基于配体的合理药物设计在α-1-肾上腺素能受体拮抗剂上的应用;李敏勇 等;《中国药科大学学报》;20050902;第36卷(第5期);第387-392页 * |
| 李敏勇 等.基于配体的合理药物设计在α-1-肾上腺素能受体拮抗剂上的应用.《中国药科大学学报》.2005,第36卷(第5期),第387-392. |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102277154A (en) | 2011-12-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104364237B (en) | Histon deacetylase (HDAC) (HDACS) inhibitor | |
| CN1090628C (en) | New N-aryl piperidine compounds, process for their preparation and pharmaceutical compositions containing them | |
| CN102277154B (en) | Phenyl piperazine small-molecule fluorescent probe of alpha1-adrenergic receptor and application thereof | |
| CN1807413B (en) | Carbazole sulfonamide derivative and its preparation method | |
| BR112016011826B1 (en) | COMPOUND, PHARMACEUTICAL COMPOSITION AND USE OF SAID COMPOUND | |
| US20080318960A1 (en) | PAR2-modulating compounds and their use | |
| Farghaly et al. | Novel sulfonyl thiazolyl-hydrazone derivatives as EGFR inhibitors: Design, synthesis, biological evaluation and molecular docking studies | |
| Ma et al. | Discovery of the first environment-sensitive near-infrared (NIR) fluorogenic ligand for α1-adrenergic receptors imaging in vivo | |
| Vettorazzi et al. | An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors | |
| JP4402191B2 (en) | Zinc fluorescent probe | |
| CN107266461A (en) | A kind of alkoxy dibenzazepines class compound, its preparation method and medical usage | |
| CN105358549A (en) | Novel quinazoline derivative | |
| CN104910894B (en) | Benzimidazole hERG potassium ion channel small-molecular fluorescent probe and preparation method and applications thereof | |
| CN106146504B (en) | A kind of heterocycle and glyoxaline compound, its pharmaceutical composition and its preparation method and application | |
| CN105062465A (en) | Environment-sensitive alpha1-adrenergic receptor near infrared fluorescence ligands and application thereof | |
| JP6021148B2 (en) | Compound transported by LST-1 and / or LST-2 | |
| FR3001967A1 (en) | PROCESS FOR THE PRODUCTION OF PYRAZOLES, NEW PYRAZOLES AND THEIR APPLICATIONS | |
| CN105343073A (en) | Compound capable of serving as Wnt signal pathway activator and preparation and application thereof | |
| CN102241969B (en) | Small-molecule fluorescent probes for quinazoline alpha1-adrenergic receptors and application of small-molecule fluorescent probes | |
| EP1650190A1 (en) | 3-aryl-3-methyl-quinoline-2,4-diones, preparation method thereof and pharmaceutical composition containing same | |
| ES2370877T3 (en) | 5-HT7 RECEIVER ANTAGONISTS | |
| CN106467545B (en) | A kind of Thienopyrimidine compound | |
| CN111423379B (en) | Substituted 3-indazole Mcl-1 protein inhibitor, preparation method and application | |
| CN103304438B (en) | N-substituted salicylamide compounds, preparation method and application | |
| JP2013516410A (en) | Molecules related to hERG ion channel and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130807 |