CN1199637C - Use of GABA transport protein inhibitor in preparing medicine for treating alcohol habituation and abuse - Google Patents
Use of GABA transport protein inhibitor in preparing medicine for treating alcohol habituation and abuse Download PDFInfo
- Publication number
- CN1199637C CN1199637C CN 02136336 CN02136336A CN1199637C CN 1199637 C CN1199637 C CN 1199637C CN 02136336 CN02136336 CN 02136336 CN 02136336 A CN02136336 A CN 02136336A CN 1199637 C CN1199637 C CN 1199637C
- Authority
- CN
- China
- Prior art keywords
- ethanol
- transport protein
- gaba
- mice
- gaba transport
- 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title claims abstract description 391
- 229960003692 gamma aminobutyric acid Drugs 0.000 title abstract description 122
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 title abstract description 117
- 108010078791 Carrier Proteins Proteins 0.000 title abstract description 101
- 102000014914 Carrier Proteins Human genes 0.000 title abstract description 92
- 239000003814 drug Substances 0.000 title abstract description 19
- 206010052804 Drug tolerance Diseases 0.000 title abstract 4
- 230000026781 habituation Effects 0.000 title abstract 4
- 229940121649 protein inhibitor Drugs 0.000 title 1
- 239000012268 protein inhibitor Substances 0.000 title 1
- QTDZOWFRBNTPQR-UHFFFAOYSA-N guvacine Chemical compound OC(=O)C1=CCCNC1 QTDZOWFRBNTPQR-UHFFFAOYSA-N 0.000 claims abstract description 25
- -1 3-nipecotic acid Chemical class 0.000 claims abstract description 8
- 239000003112 inhibitor Substances 0.000 claims description 32
- XIWBSOUNZWSFKU-UHFFFAOYSA-N ethyl piperidine-3-carboxylate Chemical compound CCOC(=O)C1CCCNC1 XIWBSOUNZWSFKU-UHFFFAOYSA-N 0.000 claims description 21
- 208000007848 Alcoholism Diseases 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 9
- XJLSEXAGTJCILF-RXMQYKEDSA-N (R)-nipecotic acid zwitterion Chemical compound OC(=O)[C@@H]1CCCNC1 XJLSEXAGTJCILF-RXMQYKEDSA-N 0.000 claims description 7
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 claims description 7
- ASVKZMUNHJQBCF-UHFFFAOYSA-N 1-ethylpiperidine formic acid Chemical compound C(=O)O.C(C)N1CCCCC1 ASVKZMUNHJQBCF-UHFFFAOYSA-N 0.000 claims description 7
- 239000004305 biphenyl Substances 0.000 claims description 7
- 206010013654 Drug abuse Diseases 0.000 claims description 6
- 235000010290 biphenyl Nutrition 0.000 claims description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 6
- 208000011117 substance-related disease Diseases 0.000 claims description 6
- QENGPZGAWFQWCZ-UHFFFAOYSA-N 3-Methylthiophene Chemical compound CC=1C=CSC=1 QENGPZGAWFQWCZ-UHFFFAOYSA-N 0.000 claims description 4
- AJIVDPRFDWUDNX-UHFFFAOYSA-N 1-(2-benzhydryloxyethyl)piperidine-3-carboxylic acid Chemical compound C1C(C(=O)O)CCCN1CCOC(C=1C=CC=CC=1)C1=CC=CC=C1 AJIVDPRFDWUDNX-UHFFFAOYSA-N 0.000 claims description 2
- MZLICCSWCLAFOT-UHFFFAOYSA-N COC1C(C(N(CC1)C(=O)O)(CC)OC)C1=CC=CC=C1 Chemical class COC1C(C(N(CC1)C(=O)O)(CC)OC)C1=CC=CC=C1 MZLICCSWCLAFOT-UHFFFAOYSA-N 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 claims description 2
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 2
- 125000004344 phenylpropyl group Chemical group 0.000 claims description 2
- OTEKOJQFKOIXMU-UHFFFAOYSA-N 1,4-bis(trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=C(C(Cl)(Cl)Cl)C=C1 OTEKOJQFKOIXMU-UHFFFAOYSA-N 0.000 claims 1
- JOCPAPMDIAWNSH-UHFFFAOYSA-N C1(=CC=C(C=C1)C1(C(CN(CC1)C(=O)O)C1=CCC1)C1=CC=C(C=C1)C)C Chemical compound C1(=CC=C(C=C1)C1(C(CN(CC1)C(=O)O)C1=CCC1)C1=CC=C(C=C1)C)C JOCPAPMDIAWNSH-UHFFFAOYSA-N 0.000 claims 1
- FHOBSYWZLTYCRW-UHFFFAOYSA-N C1(=CC=CC=C1)C1(C(C=C1)N1CC(C(=O)O)CCC1)C1=CC=CC=C1 Chemical compound C1(=CC=CC=C1)C1(C(C=C1)N1CC(C(=O)O)CCC1)C1=CC=CC=C1 FHOBSYWZLTYCRW-UHFFFAOYSA-N 0.000 claims 1
- KQTDVGXLQLLNOB-UHFFFAOYSA-N [O].C1(=CC=CC=C1)C=CC1=CC=CC=C1 Chemical compound [O].C1(=CC=CC=C1)C=CC1=CC=CC=C1 KQTDVGXLQLLNOB-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 19
- 230000006870 function Effects 0.000 abstract description 7
- JAEIBKXSIXOLOL-UHFFFAOYSA-N pyrrolidin-1-ium-3-carboxylate Chemical compound OC(=O)C1CCNC1 JAEIBKXSIXOLOL-UHFFFAOYSA-N 0.000 abstract description 5
- SXXLKZCNJHJYFL-UHFFFAOYSA-N 4,5,6,7-tetrahydro-[1,2]oxazolo[4,5-c]pyridin-5-ium-3-olate Chemical compound C1CNCC2=C1ONC2=O SXXLKZCNJHJYFL-UHFFFAOYSA-N 0.000 abstract description 4
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 101000799461 Homo sapiens Thrombopoietin Proteins 0.000 abstract description 3
- 102100034195 Thrombopoietin Human genes 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 abstract 4
- 241000699670 Mus sp. Species 0.000 description 64
- 230000001684 chronic effect Effects 0.000 description 28
- 238000002347 injection Methods 0.000 description 26
- 239000007924 injection Substances 0.000 description 26
- 230000014509 gene expression Effects 0.000 description 25
- 241000699660 Mus musculus Species 0.000 description 22
- 238000011830 transgenic mouse model Methods 0.000 description 22
- 206010012335 Dependence Diseases 0.000 description 21
- 241000699666 Mus <mouse, genus> Species 0.000 description 20
- 230000000694 effects Effects 0.000 description 20
- 230000035945 sensitivity Effects 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 238000010521 absorption reaction Methods 0.000 description 15
- 210000003568 synaptosome Anatomy 0.000 description 15
- 230000001154 acute effect Effects 0.000 description 14
- 238000002474 experimental method Methods 0.000 description 14
- 201000009032 substance abuse Diseases 0.000 description 14
- 238000012360 testing method Methods 0.000 description 14
- NGNALWDRPKNJGR-UHFFFAOYSA-N 1-[2-[(diphenylmethylene)amino]oxyethyl]-3,6-dihydro-2H-pyridine-5-carboxylic acid Chemical compound C1C(C(=O)O)=CCCN1CCON=C(C=1C=CC=CC=1)C1=CC=CC=C1 NGNALWDRPKNJGR-UHFFFAOYSA-N 0.000 description 13
- 230000004853 protein function Effects 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- 230000007774 longterm Effects 0.000 description 8
- 102000037078 GABA transporters Human genes 0.000 description 7
- 108091006228 GABA transporters Proteins 0.000 description 7
- 210000004556 brain Anatomy 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 230000034994 death Effects 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 230000000630 rising effect Effects 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- 229960003086 naltrexone Drugs 0.000 description 6
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 6
- 238000001543 one-way ANOVA Methods 0.000 description 6
- 230000002018 overexpression Effects 0.000 description 6
- 230000004952 protein activity Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 241001597008 Nomeidae Species 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- MZSOXGPKUOAXNY-UHFFFAOYSA-N coumarin 6h Chemical compound C1CCC2=C(OC(=O)C=C3)C3=CC3=C2N1CCC3 MZSOXGPKUOAXNY-UHFFFAOYSA-N 0.000 description 5
- 230000035622 drinking Effects 0.000 description 5
- 230000001939 inductive effect Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 230000004060 metabolic process Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 102000006602 glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 4
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 4
- 230000000155 isotopic effect Effects 0.000 description 4
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 4
- 231100000636 lethal dose Toxicity 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 210000002182 synaptic membrane Anatomy 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- 239000008896 Opium Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 206010001584 alcohol abuse Diseases 0.000 description 3
- 208000025746 alcohol use disease Diseases 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 230000002860 competitive effect Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 235000013922 glutamic acid Nutrition 0.000 description 3
- 239000004220 glutamic acid Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 230000036963 noncompetitive effect Effects 0.000 description 3
- 229960001027 opium Drugs 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000003757 reverse transcription PCR Methods 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 2
- VDLDUZLDZBVOAS-UHFFFAOYSA-N 1-[2-[tris(4-methoxyphenyl)methoxy]ethyl]piperidine-3-carboxylic acid Chemical compound C1=CC(OC)=CC=C1C(C=1C=CC(OC)=CC=1)(C=1C=CC(OC)=CC=1)OCCN1CC(C(O)=O)CCC1 VDLDUZLDZBVOAS-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000699802 Cricetulus griseus Species 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 102100034343 Integrase Human genes 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 102000003840 Opioid Receptors Human genes 0.000 description 2
- 108090000137 Opioid Receptors Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 2
- 235000013290 Sagittaria latifolia Nutrition 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 235000015246 common arrowhead Nutrition 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- AUZONCFQVSMFAP-UHFFFAOYSA-N disulfiram Chemical compound CCN(CC)C(=S)SSC(=S)N(CC)CC AUZONCFQVSMFAP-UHFFFAOYSA-N 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000004149 ethanol metabolism Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000010185 immunofluorescence analysis Methods 0.000 description 2
- 231100000518 lethal Toxicity 0.000 description 2
- 230000001665 lethal effect Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- YGSGYHVRPZQCTG-UHFFFAOYSA-N 1-(4,4-diphenylbut-3-enyl)-2h-pyridine-3-carboxylic acid Chemical compound C1C(C(=O)O)=CC=CN1CCC=C(C=1C=CC=CC=1)C1=CC=CC=C1 YGSGYHVRPZQCTG-UHFFFAOYSA-N 0.000 description 1
- NNHFTYXKYCVPFN-UHFFFAOYSA-N 1-(4,4-diphenylbut-3-enyl)-3,6-dihydro-2h-pyridine-5-carboxylic acid Chemical compound C1C(C(=O)O)=CCCN1CCC=C(C=1C=CC=CC=1)C1=CC=CC=C1 NNHFTYXKYCVPFN-UHFFFAOYSA-N 0.000 description 1
- QXZRDASZZSRLBB-UHFFFAOYSA-N 1-[2-(2,2-diphenylethenoxy)ethyl]piperidine-3-carboxylic acid Chemical compound C1C(C(=O)O)CCCN1CCOC=C(C=1C=CC=CC=1)C1=CC=CC=C1 QXZRDASZZSRLBB-UHFFFAOYSA-N 0.000 description 1
- PIZTUXYVFZXAFQ-UHFFFAOYSA-N 1-[2-(benzhydrylideneamino)oxyethyl]piperidine-3-carboxylic acid Chemical compound C1C(C(=O)O)CCCN1CCON=C(C=1C=CC=CC=1)C1=CC=CC=C1 PIZTUXYVFZXAFQ-UHFFFAOYSA-N 0.000 description 1
- SDJIRAOLDYSMNA-UHFFFAOYSA-N 1-[2-[2-(N-phenylanilino)ethoxy]ethyl]piperidine-3-carboxylic acid Chemical compound C1C(C(=O)O)CCCN1CCOCCN(C=1C=CC=CC=1)C1=CC=CC=C1 SDJIRAOLDYSMNA-UHFFFAOYSA-N 0.000 description 1
- PDWYUQWCERDHRZ-UHFFFAOYSA-N 1-[2-[9-(4-methoxyphenyl)fluoren-9-yl]oxyethyl]piperidine-3-carboxylic acid Chemical compound C1=CC(OC)=CC=C1C1(OCCN2CC(CCC2)C(O)=O)C2=CC=CC=C2C2=CC=CC=C21 PDWYUQWCERDHRZ-UHFFFAOYSA-N 0.000 description 1
- CMHQDSBIBSKHFP-UHFFFAOYSA-N 1-[2-[bis[4-(trifluoromethyl)phenyl]methoxy]ethyl]-3,6-dihydro-2H-pyridine-5-carboxylic acid Chemical compound C1C(C(=O)O)=CCCN1CCOC(C=1C=CC(=CC=1)C(F)(F)F)C1=CC=C(C(F)(F)F)C=C1 CMHQDSBIBSKHFP-UHFFFAOYSA-N 0.000 description 1
- XZZYCJOGZYEPPW-UHFFFAOYSA-N 1-[3-(9-carbazolyl)propyl]-4-(2-methoxyphenyl)-4-piperidinol Chemical compound COC1=CC=CC=C1C1(O)CCN(CCCN2C3=CC=CC=C3C3=CC=CC=C32)CC1 XZZYCJOGZYEPPW-UHFFFAOYSA-N 0.000 description 1
- QWORJCLBNJDDNK-UHFFFAOYSA-N 1-[4,4-bis(2-methylphenyl)but-3-enyl]piperidine-3-carboxylic acid Chemical compound CC1=CC=CC=C1C(C=1C(=CC=CC=1)C)=CCCN1CC(C(O)=O)CCC1 QWORJCLBNJDDNK-UHFFFAOYSA-N 0.000 description 1
- CNRNYORZJGVOSY-UHFFFAOYSA-N 2,5-diphenyl-1,3-oxazole Chemical compound C=1N=C(C=2C=CC=CC=2)OC=1C1=CC=CC=C1 CNRNYORZJGVOSY-UHFFFAOYSA-N 0.000 description 1
- FCCLVOJEINBTBU-UHFFFAOYSA-N 2-(3,3-diphenylpropyl)-1,2,3,6-tetrahydropyridine-5-carboxylic acid;hydrochloride Chemical compound Cl.N1CC(C(=O)O)=CCC1CCC(C=1C=CC=CC=1)C1=CC=CC=C1 FCCLVOJEINBTBU-UHFFFAOYSA-N 0.000 description 1
- OUENRUZPZZFMCA-YFKPBYRVSA-N 2-[(3s)-pyrrolidin-1-ium-3-yl]acetate Chemical compound OC(=O)C[C@@H]1CCNC1 OUENRUZPZZFMCA-YFKPBYRVSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- ZXGXTTFJFGHGTL-UHFFFAOYSA-N 4,5,6,7-tetrahydro-[1,2]thiazolo[4,5-c]pyridin-5-ium-3-olate Chemical compound C1CNCC2=C1SN=C2O ZXGXTTFJFGHGTL-UHFFFAOYSA-N 0.000 description 1
- QMRMUNWFODMEOB-UHFFFAOYSA-N 5-(4,4-diphenylbut-3-enyl)-6,7-dihydro-4h-[1,2]oxazolo[4,5-c]pyridin-3-one Chemical compound C1C=2C(=O)NOC=2CCN1CCC=C(C=1C=CC=CC=1)C1=CC=CC=C1 QMRMUNWFODMEOB-UHFFFAOYSA-N 0.000 description 1
- 206010000087 Abdominal pain upper Diseases 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- DEGMILQNXHRUSN-UHFFFAOYSA-N C1C(C(=O)O)CCCN1CCOCCC(C=1C=CC=CC=1)C1=CC=CC=C1 Chemical compound C1C(C(=O)O)CCCN1CCOCCC(C=1C=CC=CC=1)C1=CC=CC=C1 DEGMILQNXHRUSN-UHFFFAOYSA-N 0.000 description 1
- BTQRMFYEEVLKMK-UHFFFAOYSA-N C1C=2C(=O)NOC=2CCCN1CCC=C(C=1C=CC=CC=1)C1=CC=CC=C1 Chemical compound C1C=2C(=O)NOC=2CCCN1CCC=C(C=1C=CC=CC=1)C1=CC=CC=C1 BTQRMFYEEVLKMK-UHFFFAOYSA-N 0.000 description 1
- UJAXSQRTPSSJPO-RXMQYKEDSA-N CN[C@H](CCC1)c2c1[o]nc2O Chemical compound CN[C@H](CCC1)c2c1[o]nc2O UJAXSQRTPSSJPO-RXMQYKEDSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 101001094079 Homo sapiens Sodium- and chloride-dependent GABA transporter 2 Proteins 0.000 description 1
- 101001094098 Homo sapiens Sodium- and chloride-dependent GABA transporter 3 Proteins 0.000 description 1
- 208000006264 Korsakoff syndrome Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 101100202329 Mus musculus Slc6a11 gene Proteins 0.000 description 1
- OAJLTKZYCPGQMS-SCSAIBSYSA-N N[C@H](CCC1)c2c1[o]nc2O Chemical compound N[C@H](CCC1)c2c1[o]nc2O OAJLTKZYCPGQMS-SCSAIBSYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- BYIUMWGGYSEOKU-UHFFFAOYSA-N O1N=CC=C1.N1CCCC=C1 Chemical compound O1N=CC=C1.N1CCCC=C1 BYIUMWGGYSEOKU-UHFFFAOYSA-N 0.000 description 1
- 0 OC1=C(COCC2)C2=S*1 Chemical compound OC1=C(COCC2)C2=S*1 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000013614 RNA sample Substances 0.000 description 1
- 101100121148 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) GAT4 gene Proteins 0.000 description 1
- 102100035242 Sodium- and chloride-dependent GABA transporter 2 Human genes 0.000 description 1
- 102100035254 Sodium- and chloride-dependent GABA transporter 3 Human genes 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 201000008485 Wernicke-Korsakoff syndrome Diseases 0.000 description 1
- 229960004047 acamprosate Drugs 0.000 description 1
- AFCGFAGUEYAMAO-UHFFFAOYSA-N acamprosate Chemical group CC(=O)NCCCS(O)(=O)=O AFCGFAGUEYAMAO-UHFFFAOYSA-N 0.000 description 1
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 229960002563 disulfiram Drugs 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound 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
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000010247 heart contraction Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 239000003402 opiate agonist Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 206010036067 polydipsia Diseases 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- PBJUNZJWGZTSKL-MRXNPFEDSA-N tiagabine Chemical compound C1=CSC(C(=CCCN2C[C@@H](CCC2)C(O)=O)C2=C(C=CS2)C)=C1C PBJUNZJWGZTSKL-MRXNPFEDSA-N 0.000 description 1
- 229960001918 tiagabine Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Images
Abstract
The present invention relates to application of a gamma-amino butyric acid (GABA) transport protein inhibiting agent for preparing medicine for treating alcohol habituation and abuse. The inhibiting agent contains all compounds, such as 3-nipecotic acid, guvacine, high beta-proline, THPO, THAO, derivatives of 3-nipecotic acid, guvacine, high beta-proline, THPO, THAO, etc. which can inhibit GABA transport protein to lead a human body to be sensitive to alcohol. An experimental result shows that the compounds for inhibiting GABA transport protein have the function of leading the human body to be sensitive to alcohol, and therefore, the intake of alcohol by the human body is reduced. Therefore, the compounds have the clinical application value for treating alcohol habituation and abuse. The compounds can be used for preparing medicine for treating alcohol habituation and abuse.
Description
Technical field
The present invention addresses biomedicine field, is the application of γ-An Jidingsuan (GABA) transporter inhibitors in preparation treatment alcohol addiction and Drug abuse specifically
Background technology:
Alcohol addiction is an important social issue with abuse always for a long time, seniority among brothers and sisters the 3rd in the abalienation disease of the U.S..Many people are running into huge stress, can habitually relieve the lonliness and grief with the way of excessive drinking when nervous or depressed, no matter this behavior is of short duration or addicted, in a word excessive consumption of alcohol to oneself and/or all can be deleterious to the people, serious entail dangers to social stability and the safety of going back.Long-term serious drinking can cause the generation of a lot of diseases, as liver cirrhosis, Wernicke-korsakoff syndrome, various cancer, heart disease, fetal alcohol symdrome etc.The generation of a lot of accidents also causes owing to drinking, and causes economy and property loss to country.Thereby people are seeking the addiction that can treat ethanol, the medicine that reduction is thirsted for ethanol always for a long time.
Though the neuro pharmacology effect to ethanol also fully understands, this process has been accelerated in scientific research in recent years.The serious hope of restriking after for example ethanol is given up may be by receptor-mediated [the Gonzalez L.P. et al. of γ-An Jidingsuan (GABA) and glutamic acid, Alcohol Clin Exp Res, 2001,25 (5Suppl ISBRA): 197S-201S], the memory of alcohol addiction may be by dopamine, Opium and the mediation of glutamic acid system, pressure inducement may be mediated by the 5-hydroxy tryptamine system the serious hope of ethanol, or and other machine-processed synergism.Thereby the addiction of treatment ethanol can reach by different approach.
Up to the present, have been found that some medicines can be used for treating the addiction of ethanol.Mainly contain following three classes: first kind is alleviating alcohol addiction sulfur (disulfiram), and it was just got permission to use clinically before 40 years.Its mechanism of action is the further metabolism of blocking-up alcohol metabolism product acetaldehyde, thereby causes acetaldehyde accumulation in vivo.Untoward reaction such as this accumulation can cause skin rubefaction, feels sick, vomiting, thereby application clinically is very restricted.In addition, also there are some researches show the curative effect of alleviating alcohol addiction sulfur unlike placebo good [Fuller R.K.et al., JAMA, 1986,256:1449-1455].Second class is an opiate receptor agonist, and wherein using maximum clinically is naltrexone (naltrexone).Nineteen ninety-five, it was used for the treatment of the addiction of ethanol by drugs approved by FDA, but its curative effect is under suspicion equally, because some result of study shows naltrexone and can not treat the long-term addiction of serious ethanol [Krystal J.H.et al., N Engl J Med, 2001,345 (24): 1734-1739; Kranzler H.R.et al., Neuropsychopharmacology, 2000,22:493-503].Naltrexone also has some side effect, as nauseating, stomachache, headache etc.In addition, because naltrexone is the antagonist of opiate receptors, therefore when using naltrexone, the analgesia effect of Opium class medicine such as morphine will be affected, and the patient when this shows effect to serious acute pain can produce trouble.The third is acamprosate, and it is the derivant of taurine, mainly acts on the glutamate receptor in the brain, regulates the transmission of glutamic acid signal, also need do further research for its curative effect.
In sum, the addiction of ethanol and abuse are a kind of important social issue, and people are striving to find the addiction of treatment ethanol and the medicine of abuse always, but regrettably not effective in cure as yet up to now very ideal medicine.
GABA is a most important inhibitory nerve mediator in the mammalian central nervous system, the biological function of GABA transport protein is that the GABA neurotransmitter by picked-up nerve synapse gap stops its neural inhibition information transmission, and then reaches and regulate intensity that nerve signal transmits and ageing.GABA transport protein hypotype I (GAT1) is most important a kind of [Radian R.et al., J Neurosci, 1990,10:1319-1330] in the GABA transport protein family (GAT1, GAT2, GAT3, GAT4).The existing report of chemical compound with specificity inhibit feature mainly is nipecotic acid and guvacine and a lot of derivants that are parent nucleus with these two kinds of chemical compounds.Also having a lot of chemical compounds in addition is inhibitor of GABA transport protein, as high β-proline, 4,5,6,7-tetrahydro-isoxazolo-[4,5-C, pentahydro-azatropylidene isoxazole alcohol and derivant thereof or the like, relevant these chemical compounds synthetic and as the research of inhibitor referring to document [Andersen K.E., et al., J.Med.Chem., 2001,44:2152-2163; Krogsgaard-Larsen P., et al., Current Pharmaceutical Design, 2000,6:1193-1209].The present invention has disclosed the γ-An Jidingsuan transporter inhibitors addiction and the abuse for the treatment of ethanol has been had potential clinical value.
Summary of the invention
For this reason, the invention provides the γ-An Jidingsuan transporter inhibitors in the addiction of preparation treatment ethanol and the application in the Drug abuse.
The chemical compound that the present invention finds above-mentioned this class to have inhibit feature can make body reduce the ethanol intake, thereby reaches the addiction of treatment ethanol and the good result of abuse.The mechanism of action of this compounds is to suppress the function of GABA transport protein, makes body very sensitive to ethanol, thereby body will reduce the intake to ethanol, thereby avoids exceedingly drinking, and reaches the addiction of treatment ethanol and the purpose of abuse.Can be confirmed by following experiment.The γ-An Jidingsuan transporter inhibitors comprises that all can reduce the chemical compound of γ-An Jidingsuan transport protein picked-up (transhipment) function, for example above-mentioned known compound nipecotic acid, guvacine, high β-proline, 4,5,6,7-tetrahydro-isoxazolo-[4,5-C, pentahydro-azatropylidene isoxazole alcohol and their derivant etc. exemplify compound structure figure referring to Fig. 1 (said derivative is not limited to these and exemplifies chemical compound).These chemical compounds can the synthetic or purchase from the market according to reported method on the aforementioned documents.The present invention chooses wherein a kind of competitive inhibitor nipecotic acid ethyl ester (being the derivant of nipecotic acid) and a kind of noncompetitive inhibitor N-(diphenyl imido grpup ethanol based)-guvacine (NO-711 is the derivant of guvacine) and measures them for example and changed the sensitivity of body to ethanol.
The present invention is at first with the experiment of synaptosome GABA transport protein Function detection, disclose acute and chronic ethanol absorption and caused the active rising of GABA transport protein, then experimental results show that with cell GABA transport protein Function detection this active change is not directly to be had an effect by ethanol and GABA transport protein, prove that with sxemiquantitative RT-PCR this effect neither change the expression of GABA transport protein, disclose ethanol with immunofluorescence technique at last and can impel GABA transport protein generation transposition (translocation), just in synaptosome, transfer on the synaptic membrane, increase effective transport protein quantity on the cell membrane, caused the enhancing of GABA transport protein function.Then the present invention tests mice to the inductive sleep response of ethanol with the competitive inhibitor (nipecotic acid ethyl ester) and the noncompetitive inhibitor (N-(diphenyl imido grpup ethanol based)-guvacine) of GABA transport protein, after the result showed that two kinds of GABA transporter inhibitors are anticipated, it is very sensitive to ethanol that mice becomes.The present invention further tests them to the inductive calmness of ethanol, sleep and lethal response with the transgenic mice of overexpression GABA transport protein I, and the result shows that the mice of GABA transport protein overexpression comparatively tolerates ethanol.At last, the present invention has confirmed that the GABA transport protein can change the sensitivity of mice to ethanol, but does not influence ethanol metabolism in vivo.The above results shows, the absorption of ethanol has strengthened the function of CNS GABA transport protein, and the power of GABA transport protein function has determined the sensitivity of mice to ethanol, therefore can change the active medicine of GABA transport protein should be able to change the sensitivity of body to ethanol, reduce the intake of body to ethanol, thereby avoid exceedingly drinking, reach the addiction of treatment ethanol and the purpose of abuse.
The addiction of the treatment ethanol of γ-An Jidingsuan transporter inhibitors and abuse are used, and the GABA transporter inhibitors medicine that can give the effective dose of patient reaches the purpose of treatment.Clinical use administering mode can be oral or injection.Oral medicine can be made into dosage forms such as tablet, capsule, powder, solution routinely, and injection can be intramuscular injection, subcutaneous injection or intravenous injection etc.
Use the γ-An Jidingsuan transporter inhibitors when addiction for the treatment of ethanol and abuse, the amount of medicine depends on the nature and extent of disease and the situation that patient has received treatment.Finally give patient how much dosage by prescription doctor decision, the clinical dosage that uses can use the GABA transporter inhibitors of 0.05-1mg every day as per kilogram of body weight.
In the addiction and Drug abuse process of preparation γ-An Jidingsuan transporter inhibitors treatment ethanol, medicine except that containing the GABA transporter inhibitors, material such as also can comprise on the pharmacology can received carrier, solvent, implant, buffer agent and stabilizing agent.So-called " pharmacology is last acceptable " is meant and do not influence the bioactive innocuous substance of GABA transporter inhibitors.Different route of administration is depended in the selection of carrier and other material.
The present invention has disclosed the GABA transporter inhibitors and has had the sensitivity of increase body to ethanol, thereby can reduce the intake of body to ethanol, avoid exceedingly drinking, reach the addiction of treatment ethanol and the purpose of abuse, for the GABA transporter inhibitors has been opened up a new application, also new research field and new medicament screen approach have been opened up for the addiction and the abuse for the treatment of ethanol clinically.This inhibitor comprises that all can suppress the GABA transport protein and have the chemical compound of increase body to ethanol sensitivity.Because the addiction and the abuse of ethanol are a kind of important social issue, do not find the very ideal medicine of curative effect up to now as yet, so people are striving to find the addiction of treatment ethanol and the medicine of abuse always.This compounds of the present invention has clinical value to the addiction and the abuse of treatment ethanol, their action site is the GABA transport protein, the function that influences the GABA transport protein through experiment confirm does not influence ethanol metabolism in vivo, thereby the side effect that can avoid alleviating alcohol addiction sulfur to occur; This compounds of the present invention itself has analgesic activity, and does not directly block opiate receptors, thereby should be unable to produce bigger influence to the analgesia effect of Opium class medicine.In view of the γ-An Jidingsuan transporter inhibitors has above advantage, therefore, this compounds is applied to prepare the addiction and the Drug abuse for the treatment of ethanol, has the wide development prospect.
Description of drawings
Fig. 1 exemplifies the inhibitor that acts on the GABA transport protein.1-3-piperidine carboxylic acid (piperidine-3-carboxylic acid, nipecotic acid, C
6H
11NO
2), the 2-guvacine (1,2,5,6-tetrahydro-pyridine-3-carboxylic acid, guvacine, C
6H
9NO
2), 3-3-piperidine ethyl formate (piperidine-3-carboxylic acid ethyl ester, ethyl nipecotate, C
8H
15NO
2), 4-N-(diphenyl imido grpup ethanol based)-guvacine (1-[2-[[(diphenyl) imino] oxy] ethyl]-3-(1,2,5,6-tetrahydropyridin-1-yl) carboxylic acid, NO-711, C
21H
22N
2O
3), 5-4, two (3 methyl thiophene base-3-the cyclobutenyl)-nipecotic acid of 4-(1-[4,4-bis-(3-methyl-thiophen-2-yl)-but-3-enyl]-piperidine-3-carboxylic acid, tiagabine, C
20H
25NO
2S
2), two (trifluoromethyl) methoxy ethyl guvacines of 6-(1,2,5,6-tetrahydro-1-{2-[bis-[4-(trifluoromethyl) phenyl] methoxy] ethyl}-3-pyridinecarboxylic acid, CI-966, C
23H
21F
6NO
3), 7-N-(diphenyl-3-cyclobutenyl)-nipecotic acid (N-(4,4-diphenyl-3-butenyl)-3-pyridinecarboxylic acid, SKF 89976A, C
22H
25NO
2), 8-N-(diphenyl-3-cyclobutenyl) guvacine (N-(4,4-diphenyl-3-butenyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid, DPB-Guvacine, C
22H
23NO
2), 9-diphenyl methoxy ethyl)-nipecotic acid (1-[2-(diphenylmethoxy) ethyl]-3-piperidinecarboxylic acid, C
21H
25NO
3), 10-benzhydrylidene base oxethyl amine piperidine carboxylic acid (1-[2-benzhydrylideneaminooxy-ethyl]-piperidine-3-carboxylic acid, C
21H
24N
2O
3), 11-stilbene oxygen base ethyl piperidine formic acid (1-[2-(2,2-diphenyl-vinyloxy)-ethyl]-piperidine-3-carboxylic acid, C
22H
25NO
3), 12-diphenylamines base oxethyl ethyl piperidine formic acid (1-[2-(2-diphenylamino-ethoxy)-ethyl]-piperidine-3-carboxylic acid, C
22H
28N
2O
3), 13-hexichol propoxyl group ethyl piperidine formic acid (1-[2-(3-diphenylpropoxy) ethyl]-piperidine-3-carboxylic acid, C
23H
29NO
3), 14-4, and 4-di-p-tolyl-3-cyclobutenyl piperidine carboxylic acid (1-(4,4-di-o-tolyl-but-3-enyl)-piperidine-3-carboxylic acid, C
24H
29NO
2), 15-6-(3,3-two phenylpropyl) guvacine (6-(3,3-diphenylpropyl) guvacine, C
21H
23NO
2), 16-2-(3,3-hexichol propoxyl group) ethyl piperidine formic acid (1-[2-(3,3-diphenyl-propoxy)-ethyl]-piperidine-3-carboxylic acid, C
23H
29NO
3), 17-(10,11-dihydro-hexichol azatropylidene base) ethoxyethyl group piperidine carboxylic acid (1-{2-[2-910,11-dihydro-dibenzo-azepin-5-yl]-ethoxy}-ethyl)-and piperidine-3-carboxylic acid, C
24H
30N
2O
3), 18-2-(9-p-methoxyphenyl) fluorenyl ethyoxyl piperidine carboxylic acid (1-{2-[9-(4-methoxyphenyl)-9H-fluoren-9-yloxy]-ethyl}-piperidine-3-carboxylic acid, SNAP 5294, C
28H
29NO
4), 19-three p-methoxyphenyl methoxy ethyl piperidine carboxylic acids (1-{2-[tris-(4-methoxyphenyl)-methoxy] ethyl}-3-piperidine-carboxylic acid, (S)-and SNAP 5114, C
30H
35NO
6), the high β-proline of 20-(pyrrolidin-3-yl-acetic acid, Homo-β-proline, C
6H
11NO
2), the 21-4,5,6,7-tetrahydro-isoxazolo-[4,5-C (4,5,6,7-tetrahydro-isoxazolo-[4,5-C]-pyridin-3-ol, THPO, C
6H
8N
2O
2), 22-pentahydro-azatropylidene isoxazole alcohol (4,5,6,7-tetrahydro-4H-isoxazolo-[4,5-C]-azepin-3-ol THAO, C
7H
10N
2O
2), the 23-4,5,6,7-tetrahydro-isothiazolo-[4,5-C (4,5,6,7-tetrahydro-isothiazolo-[4,5-C]-pyridin-3-ol, Thio-THPO, C
6H
8N
2OS), 24-pentahydro--4-amido benzoisoxazole alcohol ((R) (-) 4-amino-3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazolo-[4,5-C]-pyridin-3-ol, (R)-Exo-THPO, C
7H
10N
2O
2), 25-pentahydro--4-methylamino benzoisoxazole alcohol ((R)-3-hydroxy-4-(1-methylamino)-4,5,6,7-tetrahydro-1,2-benzisoxazolo-[4,5-C]-pyridm-3-ol, (R)-N-Me-Exo-THPO, C
8H
12N
2O
2), 26-4,4-diphenyl-3-cyclobutenyl tetrahydropyridine isoxazole alcohol (5-(4,4-diphenyl-but-3-enyl)-4,5,6,7-tetrahydro-isoxazolo-[4,5-C]-pyridin-3-ol, DPB-THPO, C
22H
22N
2O
2), 27-diphenyl-3-cyclobutenyl pentahydro-azatropylidene isoxazole alcohol (5-(4,4-diphenyl-but-3-enyl)-5,6,7,8-tetrahydro-4H-isoxazolo-[4,5-C]-azepin-3-ol, DPB-THAO, C
23H
24N
2O
2), 28-3-azepine fluorenyl-4-o-methoxyphenyl-pyridine alcohol (1-(3-carbazol-9-yl-prophl)-4-(2-methoxyphenyl)-piperidin-4-ol, NNC 05-2090, C
27H
30N
2O
2).
Fig. 2 shows that acute alcohol is taken in after 15 minutes and long-term chronic ethanol is taken in the variation that causes GABA transport protein function, the result shows acute alcohol absorption GABA transport speed quickening after 15 minutes, show acute alcohol absorption GABA transport protein transport activity rising after 15 minutes, (a), long-term chronic ethanol is taken in back GABA transport speed and is also accelerated, show that long-term chronic ethanol absorption back GABA transport protein transport activity raises, (b), but do not cause the variation of Michaelis constant Km, (c), rectilinear wherein is that v is to v/[s] graphing method, slope is-the Km value), (n=8
*Expression p＜0.05, ethanol is to normal saline, one-way ANOVA estimates significance).
The GABA transport speed of the GABA transport speed that Fig. 3 shows G1 cell when containing 20mM with 100mM ethanol when alcohol-free is the same, show that the existence of ethanol does not influence the activity of GABA transport protein, this result has proved that ethanol and GABA transport protein I are at external not direct interaction.(a) time graph, (b) kinetic curve, rectilinear wherein are that v is to v/[s] graphing method, slope is-the Km value.G1 refers to the Chinese hamster ovary celI of stably express GABA transport protein I.
(a) shows with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to be quantitative benchmark among Fig. 4, chronic ethanol is taken in and is not caused that (first in (a) classifies DNA standard sample: 2000bp as to GABA transport protein I (GAT1) in the rna level change of Expression, 1000bp, 750bp, 500bp, 250bp, 100bp).(b) shows that acute and chronic ethanol absorption back GABA transport protein I is positioned at a side (arrow head indication) of synaptosome among Fig. 4, and the GABA transport protein I of alcohol-free absorption is positioned at whole synaptosome (arrow indication), illustrate that acute and chronic ethanol absorption back GABA transport protein I transfers on the synaptic membrane in synaptosome, scale is 1 μ m.
The mice that Fig. 5 shows injection nipecotic acid ethyl ester shortens (a) than the mice of injecting normal saline time delay behind alcohol injection, and prolong (b) length of one's sleep, show the nipecotic acid ethyl ester make mice to the ethanol sensitivity (n=10,
*Expression p＜0.05, the nipecotic acid ethyl ester is to normal saline, one-wayANOVA estimates significance).
Fig. 6 shows that the mice of injecting NO-711 shortens (a) than the mice of injecting normal saline time delay behind alcohol injection, and prolong (b) length of one's sleep, show NO-711 make mice to the ethanol sensitivity (n=10,
*Expression p＜0.05,
*Expression p＜0.01, NO-711 is to normal saline, one-way ANOVA estimates significance).
(a) shows that GABA transport protein activity is enhanced in the Transgenic Mice Brain of GABA transport protein I overexpression among Fig. 7, the transgenic mice comparison that chronic ethanol is taken in according to transgenic mice GABA transport protein function further raise (n=6,
*Expression p＜0.05, transgenic mice is to normal mouse, and represents p＜0.05, and chronic ethanol is taken in transgenic mice to normal transgenic mice, one-wayANOVA estimates significance).(b) after demonstration GABA transport protein activity raises the inductive motor capacity forfeiture of ethanol effect is weakened, show that the active rising of GABA transport protein makes mice to ethanol generation tolerance to a certain degree.(n=8,
*Mice is taken in to normal mouse in expression p＜0.05, transgenic mice and chronic ethanol, and one-way ANOVA estimates significance).(c) show to strengthen the time delay that has prolonged the ethanol induced hypnotic after the GABA transport protein function, (d) show to strengthen and to have shortened ethanol inductive length of one's sleep after the GABA transport protein function, it is responsive that the use of nipecotic acid ethyl ester can make the high mice of GABA transport protein function that ethanol is produced equally, these results show that the active height of GABA transport protein has determined the sensitivity (n=6 of mice to ethanol
*Expression p＜0.05,
*Expression p＜0.01, dissimilar mice contrasts; represents p＜0.05, and represents p＜0.01, and mice nipecotic acid ethyl ester of the same race is to normal saline, and one-way ANOVA estimates significance).
Fig. 8 is presented under the active high situation of GABA transport protein, the time-to-live of mice obviously prolongs, dead quickening rapidly after blocking GABA transport protein activity with inhibitor, this result shows that equally the active height of GABA transport protein has determined the sensitivity of mice to ethanol.
Fig. 9 is presented at mouse death rate reduction under the active high situation of GABA transport protein, and half lethal dose raises, and this result shows that the active rising of GABA transport protein can cause the ethanol tolerance.
Figure 10 shows that the pretreated normal mouse of transgenic mice and inhibitor compares with normal mouse, and alcohol content does not have significant difference in 1 hour and the 3 hours blood behind alinjection, shows that the GABA transport protein is active irrelevant with alcohol metabolism.
The specific embodiment
The source of the used medicine of following examples: the nipecotic acid ethyl ester is available from ACROS company, and NO-711 is available from Sigma company.Testing used animal is: C57BL/6J mice (CB), chronic ethanol is taken in C57BL/6J mice (CBec), acute alcohol is taken in C57BL/6J mice (CBea), transgenic mice (TG1), the normal mouse consistent (WT) with transgenic mice genetic background, chronic ethanol is taken in transgenic mice (TG1ec), and chronic ethanol is taken in the normal mouse (WTec) consistent with transgenic mice genetic background.
Injection preparation among the embodiment: nipecotic acid ethyl ester, NO-711 and ethanol are dissolved in normal saline respectively, the nipecotic acid ethyl ester is made into the solution that concentration is 3mg/ml, NO-711 is made into the solution that concentration is 0.25mg/ml, and ethanol is made into the solution that concentration is 20% (v/v).
Acute and chronic ethanol is taken in and is caused the active experiment that raises of CNS GABA transport protein
Experimental implementation is as follows: (1) adds final concentration in the normal drinking-water of mice be 20% (v/v) ethanol, and mice is taken in ethanol two months continuously, and these mices are the mice that chronic ethanol is taken in; Acute alcohol take in mice be mice at preceding 15 minutes lumbar injection ethanol 2.4g/kg of experiment, contrast then injecting normal saline.(2) disconnected neck is put to death mice, takes out full brain rapidly, and homogenate is 12-15 time in homogenate buffer (0.32M sucrose, 10mM glucose are regulated PH to 7.4 with Tris-HCl), and tissue is 1: 9 with the weight ratio of homogenate buffer, operates in the ice bath and carries out.(3) with the rotating speed of 1100g in refrigerated centrifuger centrifugal 12 minutes, take out supernatant, with the rotating speed of 10000g in refrigerated centrifuger centrifugal 20 minutes, abandon supernatant, precipitation is with artificial cerebrospinal fluid (126.6mM NaCl, 27.4mMNaHCO
3, 2.4mM KCl, 0.49mM KH
2PO
4, 1.2mM CaCl
2, 0.83mM MgCl
2, 0.49mM Na
2HPO
4, the 7.1mM glucose, PH 7.2-7.4 uses 95%O
2/ 5%CO
2Saturated) suspend, be the synaptosome suspension, measure the protein concentration of each sample with BCA protein analysis test kit (Perice company).(4) be that 0.75mg/ml carries out GABA transport function mensuration with the protein concentration, synaptosome is earlier 37 ℃ of insulations 5 minutes.For time graph, add concentration and be 40nm GABA and
3The H-GABA mixture (
3H-GABA is 4nM), 37 ℃ of reactions 0.5,1,2,3,4 and 5 minute; For kinetic curve, add concentration be respectively 40nM, 100nM, 400nM, 1 μ M, 4 μ M, 10 μ M, 20 μ M, 30 μ M and 40 μ M GABA and
3The H-GABA mixture (
3H-GABA remains 4nM), 37 ℃ of reactions 5 minutes.Use bull cell harvesting instrument (Shaoxin City satellite armarium Manufacturing Co., Ltd) that synaptosome is adsorbed onto on the film at last, film is placed on scintillation solution (2,5-diphenyl-oxazole 3.6g, 1,4-pair-[5-Ben Ji Evil base-2] benzene 0.36g, the 300ml triton x-100,600ml dimethylbenzene) in, (the sample isotope is measured 100 μ l mensuration to measure isotopic mass (CPM) with liquid scintillation instrument (Beckman company), total isotope is measured 4 μ l mensuration), calculate the GABA transport activity, reduction formula is: 0.053 * sample isotopic mass * GABA concentration/total isotopic mass (pmol/mg protein).
Measurement result: time graph show acute alcohol take in 15 minutes after and long-term chronic ethanol take in all cause the GABA transport speed accelerate (among Fig. 2 (a) and (b),
*Expression p＜0.05), shows that acute alcohol and long-term chronic ethanol absorption can both cause the increased functionality of GABA transport protein; Kinetic curve shows that long-term chronic ethanol is taken in and causes the GABA transport speed to accelerate, but do not cause Michaelis constant Km variation (among Fig. 2 (c),
*Expression p＜0.05).
Proof ethanol and GABA transport protein I (GAT1) are in the experiment of external whether direct interaction
Experimental implementation is as follows: (1) cultivates the Chinese hamster ovary celI (G1 cell) of stably express GABA transport protein I in 48 porocyte culture plates, tests and changes serum-free medium in preceding 3 hours into.(2) remove culture medium, with phosphate buffer (PBS) washing three times, add respectively in every hole and contain 20mM, 100mM ethanol or nonalcoholic Hank ' s salt buffer (HBSS) 100 μ l, room temperature was placed 10 minutes.(3) for time graph, add concentration and be 40nm GABA and
3The H-GABA mixture (
3H-GABA is 4nM), room temperature reaction 2.5,5,10,15,20,25 and 30 minutes; For kinetic curve, add concentration be respectively 40nM, 100nM, 400nM, 1 μ M, 4 μ M, 10 μ M, 20 μ M, 30 μ M and 40 μ M GABA and
3The H-GABA mixture (
3H-GABA remains 4nM), room temperature reaction 30 minutes.(Shaoxin City satellite armarium Manufacturing Co., Ltd) takes out dereaction liquid with vacuum pump, with PBS washing three times.(4) NaOH of adding 100 μ l 2N in every hole, the room temperature cracking moved into sample in the scintillation solution after 30 minutes, measured isotopic mass with liquid scintillation instrument (Beckman company), calculated GABA transport activity (similar to Example 1).
Measurement result: the GABA transport speed of the GABA transport speed that time graph (among Fig. 3 (a)) and kinetic curve (among Fig. 3 (b)) result show G1 cell when containing 20mM with 100mM ethanol when alcohol-free is the same, show that the existence of ethanol does not influence the activity of GABA transport protein, this result has proved that ethanol and GABA transport protein I are at external not direct interaction.
Acute and chronic ethanol is taken in and is impelled GABA transport protein I to transfer to experiment on the synaptic membrane in the synaptosome
Experimental implementation is as follows: 1.RT-PCR analyzes (1) disconnected neck and puts to death chronic ethanol and take in mice and control mice, takes out full brain rapidly, and fully homogenate in Trizol reagent (GIBCO company) extracts total RNA according to the RNA method for extracting of routine.(2) total RNA sample was handled reuse phenol/chloroform extracting and purifying with the DNA enzyme of no RNA enzyme 45 minutes at 37 ℃.(3) with M-MLV reverse transcriptase (GIBCO company) 37 ℃ of reverse transcriptions 90 minutes, the deactivation reverse transcriptase, the gained sample is the cDNA sample.(4) do the PCR reaction, the primer of GABA transport protein I is: 5 ' ACCAAGCTTAGGCTGCAAAGCTGCTG3 ', the primer of 5 ' AGGCCTTTGAACATGGGCGCCAG3 ' GAPDH is: 5 ' ACGACCCCTTCATTGACC3 ', 5 ' AGACACCAGTAGACTCCACG3 '.Reaction condition is: 94 ℃ 45 seconds, 60 ℃ 45 seconds, 72 ℃ 1 minute.(5) the PCR product carries out agarose electrophoretic analysis, with molecule image system (Bio-Rad company) quantitative amount of product amount.2. immunofluorescence analysis (1) extracts synaptosome by embodiment 1 described method.(2) the synaptosome sample is coated on the microscope slide of gelatin bag quilt 37 ℃ of oven dry.(3) carry out immunoreation, synaptosome is earlier with serum room temperature sealing 1 hour, then with anti-GABA transport protein I antibody be incubated overnight (4 ℃).(4) with after the PBS washing, sample and the two anti-room temperature reactions that connect biotin 2 hours.(5) with after the PBS washing, the plain room temperature reaction of the affinity of sample and FITC labelling 1 hour.(6) with the PBS washing, the mountant mounting is observed under fluorescence microscope, and is taken pictures.
Measurement result: it is quantitative benchmark that the RT-PCR electrophoresis result shows with GAPDH, the expression no significant difference (among Fig. 4 (a)) of the expression of the GABA transport protein I of chronic ethanol absorption mice and the GABA transport protein I of control mice shows that chronic ethanol absorption does not cause GABA transport protein I change of Expression.The immunofluorescence analysis result shows that acute and chronic ethanol absorption back GABA transport protein I is positioned at a side (arrow head indication) of synaptosome, and the GABA transport protein I of alcohol-free absorption is positioned at whole synaptosome (arrow portion indication) (among Fig. 4 (b)), illustrates that acute and chronic ethanol absorption back GABA transport protein I transfers on the synaptic membrane in synaptosome.
By mice after the pretreatment of sleep experiments test GABA transport protein I competitive inhibitor nipecotic acid ethyl ester to the sensitivity of ethanol
Experimental implementation is as follows: (1) is to mouse peritoneal injection nipecotic acid ethyl ester 60mg/kg, the normal saline of matched group lumbar injection equal volume.Give injected in mice ethanol 3.6g/kg after (2) 10 minutes, immediately mice is lain on the back in " V " type groove, record can not right the time of oneself from the alcohol injection to the mice, be called time delay; Record can not right own to the time that can right oneself again from mice, be called the length of one's sleep.Can the index that right be right in 30 seconds 3 times.
Test result: the mice of injection nipecotic acid ethyl ester than the mice of injecting normal saline shorten time delay behind alcohol injection (among Fig. 5 (a),
*Expression p＜0.05), prolong the length of one's sleep (among Fig. 5 (b),
*Expression p＜0.05), show that the nipecotic acid ethyl ester makes mice to the ethanol sensitivity.
By mice after sleep experiments test GABA transport protein I noncompetitive inhibitor N-(diphenyl imido grpup ethanol based)-guvacine pretreatment to the sensitivity of ethanol
Experimental implementation is as follows: (1) is to mouse peritoneal injection NO-7115mg/kg, the normal saline of matched group lumbar injection equal volume.Give injected in mice ethanol 3.6g/kg after (2) 10 minutes, immediately mice is lain on the back in " V " type groove, record can not right the time of oneself from the alcohol injection to the mice, be called time delay; Record can not right own to the time that can right oneself again from mice, be called the length of one's sleep.Can the index that right be right in 30 seconds 3 times.
Test result: the mice of injection NO-711 than the mice of injecting normal saline shorten time delay behind alcohol injection (among Fig. 6 (a),
*Expression p＜0.05,
*Expression p＜0.01), prolong the length of one's sleep (among Fig. 6 (b),
*Expression p＜0.05,
*Expression p＜0.01), shows that NO-711 makes mice to the ethanol sensitivity.
By the sensitivity of the mice after freely-movable experiment and active rising of sleep experiments test GABA transport protein I to ethanol
Experimental implementation is as follows: the acquisition of the transgenic mice that active (1) the chronic ethanol that raises of the transgenic mice of 1.GABA transport protein I overexpression GABA transport protein in brain is taken in is with the acquisition of the normal mouse of chronic ethanol absorption among the embodiment 1.(2) the active mensuration of GABA transport protein is with embodiment 1.2. freely-movable experiment (1) is put into an open chest with mice, and chest is of a size of 50 * 50 * 30cm, and the bottom is divided into the grid of 10 * 10cm, the number of squares that the record mice crossed in 5 minutes.(2) giving mouse peritoneal alcohol injection 1.75g/kg, put back to immediately in the chest, is time zero with the alinjection, is recorded in respectively 2-7 minute, 12-17 minute, 32-37 minute and the record mice crosses in 60-65 minute time period number of squares.(3) calculate mice behind alinjection with respect to active percentage rate before the alinjection.3. the sleep experiments operation is with embodiment 4.
The GABA transport speed is faster than normal mouse in the Transgenic Mice Brain of the apparent not GABA transport protein I overexpression of test result: GABA transhipment time graph, and the transgenic mice GABA transport speed that chronic ethanol is taken in comparison is fast (among Fig. 7 (a) according to transgenic mice
*Expression p＜0.05, represents p＜0.05), showing that GABA transport protein activity is enhanced in the Transgenic Mice Brain of GABA transport protein I overexpression, chronic ethanol is taken in the function that can further strengthen the GABA transport protein.The freely-movable experimental result show the GABA transport protein active raise the back to the inductive motor capacity forfeiture of ethanol effect weaken (among Fig. 7 (b),
*Expression p＜0.05), shows that active rising of GABA transport protein makes mice to ethanol generation tolerance to a certain degree.The sleep experiments result shows that strengthening GABA transport protein function has prolonged time delay (among Fig. 7 (c)), has shortened the length of one's sleep (among Fig. 7 (d)), the use of nipecotic acid ethyl ester confirmed again embodiment 4 the result (among Fig. 7 (c) and (d),
*Expression p＜0.05,
*Expression p＜0.01, represents p＜0.05, represents p＜0.01), these results show that the active height of GABA transport protein has determined the sensitivity of mice to ethanol.
Active and the lethal relation of high dose ethanol of GABA transport protein
Experimental implementation is as follows: (1) is put back to mice in the cage immediately to the nipecotic acid ethyl ester of mouse peritoneal injection 9g/kg or the normal saline of equal volume.(2) death time of every mice of record, stop as judgment criteria with heart beating.(3) in the statistics different time sections on the same group mice survive number.
Test result: under the active high situation of GABA transport protein, the time-to-live of mice obviously prolongs, dead accelerate rapidly (Fig. 8) after blocking GABA transport protein activity with inhibitor, this result shows that equally the active height of GABA transport protein has determined the sensitivity of mice to ethanol.
The relation of GABA transport protein activity and ethanol half lethal dose
Experimental implementation is as follows: (1) to mouse peritoneal injection 6.5,7.0, the ethanol of 7.5g/kg is put back to mice in the cage immediately respectively.(2) every group of dead mouse number of record calculated mortality rate.(3) half lethal dose (LD is calculated in mapping
50).
Test result: mouse death rate reduces under the active high situation of GABA transport protein, and half lethal dose raises (Fig. 9), and this result shows that the active rising of GABA transport protein can cause the ethanol tolerance.
The active height of GABA transport protein is irrelevant with alcohol metabolism
Experimental implementation is as follows: (1) is put back to mice in the cage immediately to the normal saline of mouse peritoneal injection 60mg/kg nipecotic acid ethyl ester or equal volume.Give the ethanol of these mouse peritoneal injections 3.6g/kg after (2) 10 minutes, immediately mice is put back in the cage.(3) put to death half mice in 1 hour behind the alinjection and get blood, second half mice was put to death behind alinjection and gets blood in 3 hours.(4) measure the content of ethanol in each mouse blood with Sigma company ethanol assay kit.
Test result: transgenic mice is compared with normal mouse with the pretreated mice of inhibitor, and alcohol content does not have significant difference (Figure 10) in 1 hour and the 3 hours blood behind alinjection, shows that the GABA transport protein is active irrelevant with alcohol metabolism.
The preparation of embodiment 10 treatment alcohol addictions and abuse of injection liquid
Nipecotic acid ethyl ester 0.75 gram, 1.25 grams, 2.5 grams distinctly are dissolved in 1 premium on currency, being distributed into the injection that 1.5mg/2ml/ props up, 2.5mg/2ml/ props up, 5mg/2ml/ props up concentration behind the mix homogeneously seals in ampoule bottle, disinfection is made product, the lucifuge preservation.
The preparation of embodiment 11 treatment alcohol addictions and abuse of injection liquid
NO-711 0.75 gram, 1.25 grams, 2.5 grams distinctly are dissolved in 1 premium on currency, are distributed into the injection that 1.5mg/2ml/ props up, 2.5mg/2ml/ props up, 5mg/2ml/ props up concentration behind the mix homogeneously and seal in ampoule bottle, disinfection is made product, the lucifuge preservation.
The preparation of embodiment 12 treatment alcohol addictions and abuse tablet
By known tabletting technology, get NO-711 10 grams, dextrin 130 grams, starch 100 grams, carboxymethyl starch 50 grams, put into pulverizer together and fully mixed 25-30 minute, be crushed to about 80-120 order, add magnesium stearate 3 grams again, uniform mixing, make 1000 tablets of tablets through pelleter, every about 0.3 gram of weight, every contains NO-711 10mg.
Claims (1)
1, the application of a kind of γ-An Jidingsuan transporter inhibitors in preparation treatment alcohol addiction and Drug abuse, wherein said γ-An Jidingsuan transporter inhibitors is selected from nipecotic acid, guvacine, the nipecotic acid ethyl ester, N-(diphenyl imido grpup ethanol based)-guvacine, 4, two (3 methyl thiophene base-3-the cyclobutenyl)-nipecotic acid of 4-, two (trifluoromethyl) methoxy ethyl guvacine, N-(diphenyl-3-cyclobutenyl)-nipecotic acid, N-(diphenyl-3-cyclobutenyl) guvacine, (diphenyl methoxy ethyl)-nipecotic acid, benzhydrylidene base oxethyl amine piperidine carboxylic acid, stilbene oxygen base ethyl piperidine formic acid, diphenylamino ethoxyethyl group piperidine carboxylic acid, hexichol propoxyl group ethyl piperidine formic acid, 4,4-di-p-tolyl-3-cyclobutenyl piperidine carboxylic acid, 6-(3,3-two phenylpropyl) guvacine, 2-(3,3-hexichol propoxyl group) ethyl piperidine formic acid, (10,11-dihydro-hexichol azatropylidene base) ethoxyethyl group piperidine carboxylic acid, 2-(9-p-methoxyphenyl) fluorenyl ethyoxyl piperidine carboxylic acid, three p-methoxyphenyl methoxy ethyl piperidine carboxylic acids.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02136336 CN1199637C (en) | 2002-08-01 | 2002-08-01 | Use of GABA transport protein inhibitor in preparing medicine for treating alcohol habituation and abuse |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02136336 CN1199637C (en) | 2002-08-01 | 2002-08-01 | Use of GABA transport protein inhibitor in preparing medicine for treating alcohol habituation and abuse |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1401319A CN1401319A (en) | 2003-03-12 |
| CN1199637C true CN1199637C (en) | 2005-05-04 |
Family
ID=4748608
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 02136336 Expired - Fee Related CN1199637C (en) | 2002-08-01 | 2002-08-01 | Use of GABA transport protein inhibitor in preparing medicine for treating alcohol habituation and abuse |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1199637C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101559054B (en) * | 2008-04-15 | 2011-04-20 | 袁才蔚 | Use of chemical compound medicament for curing alcohol dependence |
| GB2601519A (en) * | 2020-12-02 | 2022-06-08 | Chemestmed Ltd | Method of support of survival and protection of neurons by RNA m6A methyltransferase complex METTL3/METTL14 activators |
-
2002
- 2002-08-01 CN CN 02136336 patent/CN1199637C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1401319A (en) | 2003-03-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Mullershausen et al. | Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors | |
| Bennett et al. | Neurotransmitter receptors in frontal cortex of schizophrenics | |
| Lal | Narcotic dependence, narcotic action and dopamine receptors | |
| Lapchak et al. | Binding sites for [3H] AF-DX 116 and effect of AF-DX 116 on endogenous acetylcholine release from rat brain slices | |
| Bai et al. | Equivalent switching dose from oral risperidone to risperidone long-acting injection: a 48-week randomized, prospective, single-blind pharmacokinetic study. | |
| CN102302493B (en) | The method of activation of progenitor cells/stem cell | |
| US9221761B2 (en) | Method for inhibition of deubiquitinating activity | |
| CN110478353B (en) | Methods of treating and preventing alloantibody-driven chronic graft-versus-host disease | |
| CN1742731A (en) | Treat the Pyrazolopyrimidinonefor of female sexual disorder | |
| De Bundel et al. | Involvement of the AT1 receptor subtype in the effects of angiotensin IV and LVV‐haemorphin 7 on hippocampal neurotransmitter levels and spatial working memory | |
| CN1319013A (en) | Pharmaceutical agents for treatment of parkinson's diseae, ADHD and microadenomas | |
| EP3436010A1 (en) | 5-ht2a serotonin receptor inverse agonists or antagonists for use in reducing amyloid-beta peptides and accumulation of amyloid plaques | |
| Saito et al. | Inhibitory effects of emedastine difumarate on histamine release | |
| CN107787227A (en) | The treatment of NUT center line cancers | |
| Lin et al. | Targeting the PI3K/STAT3 axis modulates age‐related differences in macrophage phenotype in rats with myocardial infarction | |
| Summers et al. | A microdialysis study of the effects of the nicotinic agonist RJR-2403 on cortical release of acetylcholine and biogenic amines | |
| CN1199637C (en) | Use of GABA transport protein inhibitor in preparing medicine for treating alcohol habituation and abuse | |
| Ohlstein et al. | Nonpeptide endothelin receptor antagonists. XI. Pharmacological characterization of SB 234551, a high-affinity and selective nonpeptide ETA receptor antagonist | |
| JP2002527357A (en) | Imidazoline receptor binding compounds | |
| Griesbacher et al. | Effects of FR173657, a non‐peptide B2 antagonist, on kinin‐induced hypotension, visceral and peripheral oedema formation and bronchoconstriction | |
| Moncada et al. | Effects of serine/threonine protein phosphatase inhibitors on morphine-induced antinociception in the tail flick test in mice | |
| US20200384005A1 (en) | Zika virus protease inhibitors and methods of use thereof | |
| Seeman | Dopamine D2High receptors moderately elevated by bifeprunox and aripiprazole | |
| Naber et al. | Naloxone treatment for five days ineffective in schizophrenia: Neuroendocrine actions of the opiate antagonist | |
| Van Bockstaele et al. | Low dose naltrexone administration in morphine dependent rats attenuates withdrawal-induced norepinephrine efflux in forebrain |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: SHANGHAI INST. OF LIFE SCIENCE, CAS; HEHONG BIOLO Free format text: FORMER OWNER: SHANGHAI INST. OF LIFE SCIENCE, CAS; SAIDA BIOLOGICAL TECHNOLOGY RESEARCH CENTER CO., LTD., SHANGHAI Effective date: 20060609 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20060609 Address after: 300031 No. 320, Yueyang Road, Shanghai Co-patentee after: Cell-star Biological Technology (Shanghai) Co., Ltd. Patentee after: Shanghai Institute of life Sciences, Chinese Academy of Sciences Address before: 200031 No. 319, Yueyang Road, Shanghai Co-patentee before: Saida Biological Technology Research Center Co., Ltd., Shanghai Patentee before: Shanghai Institute of life Sciences, Chinese Academy of Sciences |
|
| DD01 | Delivery of document by public notice |
Addressee: Wang Yu Document name: Notification of Passing Examination on Formalities |
|
| ASS | Succession or assignment of patent right |
Owner name: ZHONGMEI GUOLIAN (SHANGHAI) BIOTECHNOLOGY RESEARCH Free format text: FORMER OWNER: HEHONG BIO-TECH (SHANGHAI) CO., LTD. Effective date: 20120312 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20120312 Address after: 200031 No. 320, Yueyang Road, Shanghai Co-patentee after: Guolian (Shanghai) Biotechnology Research Co., Ltd. Patentee after: Shanghai Institute of life Sciences, Chinese Academy of Sciences Address before: 200031 No. 320, Yueyang Road, Shanghai Co-patentee before: Hehong Biotechnology (Shanghai) Co., Ltd. Patentee before: Shanghai Institute of life Sciences, Chinese Academy of Sciences |
|
| DD01 | Delivery of document by public notice |
Addressee: Wang Yu Document name: Notification of Passing Examination on Formalities |
|
| C56 | Change in the name or address of the patentee | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 200031 No. 320, Yueyang Road, Shanghai Patentee after: Shanghai Institute of life Sciences, Chinese Academy of Sciences Patentee after: Shanghai United Stem Cell Technology Co., Ltd. Address before: 200031 No. 320, Yueyang Road, Shanghai Patentee before: Shanghai Institute of life Sciences, Chinese Academy of Sciences Patentee before: Guolian (Shanghai) Biotechnology Research Co., Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20050504 Termination date: 20160801 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |