CN101224201B - 多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂的应用 - Google Patents
多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂的应用 Download PDFInfo
- Publication number
- CN101224201B CN101224201B CN2007100366018A CN200710036601A CN101224201B CN 101224201 B CN101224201 B CN 101224201B CN 2007100366018 A CN2007100366018 A CN 2007100366018A CN 200710036601 A CN200710036601 A CN 200710036601A CN 101224201 B CN101224201 B CN 101224201B
- Authority
- CN
- China
- Prior art keywords
- disease
- transporter
- dopamine
- norepinephrine
- cell
- 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
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 title description 32
- 229960003638 dopamine Drugs 0.000 title description 16
- 229960002748 norepinephrine Drugs 0.000 title description 12
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 title description 10
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 title description 10
- 238000012546 transfer Methods 0.000 title description 6
- 229940125436 dual inhibitor Drugs 0.000 title 1
- 102000004169 proteins and genes Human genes 0.000 title 1
- 108090000623 proteins and genes Proteins 0.000 title 1
- 239000003814 drug Substances 0.000 claims abstract description 43
- 102000006441 Dopamine Plasma Membrane Transport Proteins Human genes 0.000 claims abstract description 42
- 108010044266 Dopamine Plasma Membrane Transport Proteins Proteins 0.000 claims abstract description 42
- 239000003112 inhibitor Substances 0.000 claims abstract description 35
- 102000008092 Norepinephrine Plasma Membrane Transport Proteins Human genes 0.000 claims abstract description 32
- 108010049586 Norepinephrine Plasma Membrane Transport Proteins Proteins 0.000 claims abstract description 32
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 29
- 238000011282 treatment Methods 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- LFYJSSARVMHQJB-UHFFFAOYSA-N Backuchiol Natural products CC(C)=CCCC(C)(C=C)C=CC1=CC=C(O)C=C1 LFYJSSARVMHQJB-UHFFFAOYSA-N 0.000 claims description 35
- LFYJSSARVMHQJB-GOSISDBHSA-N bakuchinol Natural products CC(C)=CCC[C@@](C)(C=C)C=CC1=CC=C(O)C=C1 LFYJSSARVMHQJB-GOSISDBHSA-N 0.000 claims description 35
- 229940117895 bakuchiol Drugs 0.000 claims description 35
- KXXXNMZPAJTCQY-UHFFFAOYSA-N bakuchiol Natural products CC(C)CCCC(C)(C=C)C=Cc1ccc(O)cc1 KXXXNMZPAJTCQY-UHFFFAOYSA-N 0.000 claims description 35
- LFYJSSARVMHQJB-QIXNEVBVSA-N bakuchiol Chemical compound CC(C)=CCC[C@@](C)(C=C)\C=C\C1=CC=C(O)C=C1 LFYJSSARVMHQJB-QIXNEVBVSA-N 0.000 claims description 21
- 208000018737 Parkinson disease Diseases 0.000 claims description 15
- 208000024827 Alzheimer disease Diseases 0.000 claims description 8
- 239000002552 dosage form Substances 0.000 claims description 8
- 238000002347 injection Methods 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 7
- 239000002775 capsule Substances 0.000 claims description 4
- 239000008187 granular material Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 239000006188 syrup Substances 0.000 claims description 4
- 235000020357 syrup Nutrition 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 15
- 210000005064 dopaminergic neuron Anatomy 0.000 abstract description 8
- 210000004027 cell Anatomy 0.000 description 40
- -1 Luo Piniluo Chemical compound 0.000 description 23
- 201000010099 disease Diseases 0.000 description 22
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 22
- 230000000694 effects Effects 0.000 description 22
- PLRACCBDVIHHLZ-UHFFFAOYSA-N 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Chemical compound C1N(C)CCC(C=2C=CC=CC=2)=C1 PLRACCBDVIHHLZ-UHFFFAOYSA-N 0.000 description 20
- 101001135571 Mus musculus Tyrosine-protein phosphatase non-receptor type 2 Proteins 0.000 description 20
- 241001465754 Metazoa Species 0.000 description 17
- 239000000203 mixture Substances 0.000 description 15
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 13
- 229960004502 levodopa Drugs 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 12
- 108010078791 Carrier Proteins Proteins 0.000 description 11
- 102000014914 Carrier Proteins Human genes 0.000 description 11
- 230000007850 degeneration Effects 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 239000008194 pharmaceutical composition Substances 0.000 description 11
- 208000001089 Multiple system atrophy Diseases 0.000 description 9
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 9
- 125000002252 acyl group Chemical group 0.000 description 8
- 229910052736 halogen Inorganic materials 0.000 description 8
- 150000002367 halogens Chemical class 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 206010012289 Dementia Diseases 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 208000023105 Huntington disease Diseases 0.000 description 6
- 206010061216 Infarction Diseases 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 102100033927 Sodium- and chloride-dependent GABA transporter 1 Human genes 0.000 description 6
- 101710104414 Sodium- and chloride-dependent GABA transporter 1 Proteins 0.000 description 6
- 108091000117 Tyrosine 3-Monooxygenase Proteins 0.000 description 6
- 102000048218 Tyrosine 3-monooxygenases Human genes 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 210000002569 neuron Anatomy 0.000 description 6
- 239000013641 positive control Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000375 suspending agent Substances 0.000 description 6
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 description 5
- 201000002832 Lewy body dementia Diseases 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 210000005036 nerve Anatomy 0.000 description 5
- 230000001575 pathological effect Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 230000000996 additive effect Effects 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 description 4
- 229960001058 bupropion Drugs 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 239000003701 inert diluent Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 229940076279 serotonin Drugs 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 210000000225 synapse Anatomy 0.000 description 4
- 238000012549 training Methods 0.000 description 4
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- 208000011990 Corticobasal Degeneration Diseases 0.000 description 3
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 description 3
- 101000631929 Homo sapiens Sodium-dependent serotonin transporter Proteins 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 208000009829 Lewy Body Disease Diseases 0.000 description 3
- 241001597008 Nomeidae Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 206010033799 Paralysis Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 102100028874 Sodium-dependent serotonin transporter Human genes 0.000 description 3
- 210000004227 basal ganglia Anatomy 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 230000002490 cerebral effect Effects 0.000 description 3
- 210000004720 cerebrum Anatomy 0.000 description 3
- 239000002131 composite material Substances 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 210000001652 frontal lobe Anatomy 0.000 description 3
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 238000003364 immunohistochemistry Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000007574 infarction Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 210000004558 lewy body Anatomy 0.000 description 3
- 230000033001 locomotion Effects 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 201000010256 myopathy, lactic acidosis, and sideroblastic anemia Diseases 0.000 description 3
- 230000004770 neurodegeneration Effects 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 208000012902 Nervous system disease Diseases 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 108010012996 Serotonin Plasma Membrane Transport Proteins Proteins 0.000 description 2
- 102000019208 Serotonin Plasma Membrane Transport Proteins Human genes 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 230000003920 cognitive function Effects 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 125000000268 heptanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 210000001320 hippocampus Anatomy 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 150000002611 lead compounds Chemical class 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 210000000478 neocortex Anatomy 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 2
- 239000003605 opacifier Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000009256 replacement therapy Methods 0.000 description 2
- 230000013275 serotonin uptake Effects 0.000 description 2
- 230000036301 sexual development Effects 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 210000003523 substantia nigra Anatomy 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229920001817 Agar Polymers 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 206010006100 Bradykinesia Diseases 0.000 description 1
- KORNTPPJEAJQIU-KJXAQDMKSA-N Cabaser Chemical compound C1=CC([C@H]2C[C@H](CN(CC=C)[C@@H]2C2)C(=O)N(CCCN(C)C)C(=O)NCC)=C3C2=CNC3=C1 KORNTPPJEAJQIU-KJXAQDMKSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 229940099362 Catechol O methyltransferase inhibitor Drugs 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- 229940122041 Cholinesterase inhibitor Drugs 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- FMGYKKMPNATWHP-UHFFFAOYSA-N Cyperquat Chemical compound C1=C[N+](C)=CC=C1C1=CC=CC=C1 FMGYKKMPNATWHP-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 241000196324 Embryophyta Species 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
- 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 1
- 229940122459 Glutamate antagonist Drugs 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000006083 Hypokinesia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010021639 Incontinence Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- 206010061533 Myotonia Diseases 0.000 description 1
- 229940099433 NMDA receptor antagonist Drugs 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000005665 Neurotransmitter Transport Proteins Human genes 0.000 description 1
- 108010084810 Neurotransmitter Transport Proteins Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229940087098 Oxidase inhibitor Drugs 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- BKRGVLQUQGGVSM-KBXCAEBGSA-N Revanil Chemical compound C1=CC(C=2[C@H](N(C)C[C@H](C=2)NC(=O)N(CC)CC)C2)=C3C2=CNC3=C1 BKRGVLQUQGGVSM-KBXCAEBGSA-N 0.000 description 1
- 241000220010 Rhode Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910000323 aluminium silicate Inorganic materials 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 229960004046 apomorphine Drugs 0.000 description 1
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- BNQDCRGUHNALGH-UHFFFAOYSA-N benserazide Chemical compound OCC(N)C(=O)NNCC1=CC=C(O)C(O)=C1O BNQDCRGUHNALGH-UHFFFAOYSA-N 0.000 description 1
- 229960000911 benserazide Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000003139 biocide Substances 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N biotin Natural products N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 229960002802 bromocriptine Drugs 0.000 description 1
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229960004596 cabergoline Drugs 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003543 catechol methyltransferase inhibitor Substances 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 239000012531 culture fluid Substances 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- MHUWZNTUIIFHAS-CLFAGFIQSA-N dioleoyl phosphatidic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC MHUWZNTUIIFHAS-CLFAGFIQSA-N 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000028436 dopamine uptake Effects 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 230000002327 eosinophilic effect Effects 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N ferric oxide Chemical compound O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000003825 glutamate receptor antagonist Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229960003587 lisuride Drugs 0.000 description 1
- PIOZZBNFRIZETM-UHFFFAOYSA-L magnesium;2-carbonoperoxoylbenzoic acid;2-oxidooxycarbonylbenzoate Chemical compound [Mg+2].OOC(=O)C1=CC=CC=C1C([O-])=O.OOC(=O)C1=CC=CC=C1C([O-])=O PIOZZBNFRIZETM-UHFFFAOYSA-L 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000001259 mesencephalon Anatomy 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000004898 mitochondrial function Effects 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 230000003961 neuronal insult Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100001083 no cytotoxicity Toxicity 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-N o-dicarboxybenzene Natural products OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 230000001144 postural effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 229960003089 pramipexole Drugs 0.000 description 1
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 210000004129 prosencephalon Anatomy 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000011506 response to oxidative stress Effects 0.000 description 1
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 1
- 229960003946 selegiline Drugs 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229940125725 tranquilizer Drugs 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
- A61K31/055—Phenols the aromatic ring being substituted by halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Emergency Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂在制备治疗中枢神经退行性疾病的药物中的应用。本发明还公开了所述多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂的药物组合物。本发明首次提出并证明了多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂保护多巴胺能神经元，为临床上治疗中枢神经退行性疾病提供了新的选择。
Description
技术领域
本发明涉及生物医药领域，具体地涉及多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂在制备治疗中枢神经系统退行性疾病药物中的应用。
背景技术
中枢神经退行性疾病对全球人口存在越来越大的威胁。世界卫生组织预测，到2040年中枢神经退行性疾病将超过癌症成为人类的第二大死因。2002年，中枢神经退行性疾病导致的全球人口死亡总数是50万人。该病主要发生在老年人，但也有一些早发病例。同时，随着人们生活水平的提高，人类生存寿命逐渐延长，从而使中枢神经退行性疾病的高危人群数量进一步增加。目前，随着社会的进步、老年人口的比例和数量不断增加，这类疾病已经成为影响人类健康水平和生活质量的重大社会问题。
中枢神经退行性疾病是可表现为多种临床症状和结果的一类疾病的总称。中枢神经系统退行性疾病大多呈进行性发展，是一类病因学和发病机制尚不清楚的疾病。它的发病机制是通过具有特定功能的神经核团发生萎缩和神经元死亡，从而引起脑损害或躯体功能障碍。目前已发现的中枢神经系统退行性疾病：阿尔茨海默病(Alzheimer disease，AD)、帕金森病(parkinson’s disease，PD)、亨廷顿病(Huntington disease，HD)、肌萎缩性脊髓侧索硬化症(amyotrophic lateral sclerosis，ALS)、Lewy体痴呆(dementia with lewy body，DL B)、多发梗死灶性痴呆(multi-infarct dementi2 a，MID)、Pick小体病(Pick bodydisease)、大脑前叶退行性变(frontal lobe degeneration，FLD)、皮层基底节退行性变(corticobasal degeneration，CBD)、多系统萎缩症(multiple system atrophy，MSA)、渐进性上运动核瘫痪(progressive supranuclear palsy，PSP)、新变异型Creutzfeldt-Jakob病(new variant Creutzfeldt-Jakob disease，nvCJD)等，目前临床上对于这类疾病尚无有效控制病程进展的措施，患者最终将丧失生活能力甚至死亡。
阿尔茨海默病(Alzheimer disease，AD)的发病率在多种退行性疾病中位居首位，是一种渐进性的神经退行性疾病，为老年性痴呆中最常见的病因。临床表现为：进行性认知功能下降，记忆和日常生活能力的丧失；晚期患者甚至不能识别家庭成员。病变最易累及的区域是与高级认知功能相关的脑区，特别是新皮层和海马。脑组织病理检查可见到相关脑区(基底前脑、海马和新皮层等)内神经突触和锥体神经元消失等。(De Strooper B，.J Cell Sci，2000，113：1857-1870；Zhang X.Curr Drug Targets CNS Neurol Disord，2004，3：137-152；MuirJL.Pharmacol Biochem Behav，1997，56：687-696.)
目前临床上，AD患者经常被给予一些辅助用药，如失禁药物，抗抑郁药或镇静药来控制某些特殊的症状，但一般有两种药物被用来控制AD的进展：胆碱脂酶抑制剂和NMDA受体拮抗剂。目前尚无能够阻断AD进展的疫苗，疗法或药物。
帕金森病(parkinson’s disease，PD)是以中脑黑质中多巴胺能神经元为主受到损伤的老年性退行性神经疾病，呈进行性发展。临床早期以锥体外系运动受损为主：运动迟缓、静止性震颤、肌强直及姿势反射障碍为临床特征，随着疾病进展，可出现认知障碍，包括痴呆、抑郁和焦虑等症状，其中对于帕金森病伴随有痴呆的病人能够占到30-60％不等，甚至有调查显示可达到93％的病人有痴呆表现；多巴胺替代治疗有效；临床发病年龄一般在60岁左右，早到40岁就可出现症状，在55岁以上有1％的罹患该病，66岁以上可达2％以上。
PD病因尚不清楚，发病机理复杂；病理特征为选择性黑质多巴胺能神经元变性丢失、残余多巴胺能神经元出现嗜酸性包涵体(lewy小体)，导致黑质纹状体系统多巴胺递质减少的生化改变。对于多巴胺能神经元选择性丢失的认识，以氧化应激反应、线粒体功能缺陷和细胞凋亡机制为基础的解释得到了大家的认可，在此认识基础上的药物治疗包括：
1)多巴胺替代治疗，如左旋多巴；
2)多巴胺受体激动剂，如溴隐亭、麦角乙脲等；
3)抗胆碱能制剂，如本海索；
4)多巴胺释放促进剂，如金刚烷胺；
4)单胺氧化酶抑制剂，如丙炔苯丙胺等；
5)儿茶酚胺氧位甲基转移酶抑制剂，如硝替卡明；
6)其它，如谷氨酸拮抗剂、抗组胺药、心得胺等；
此外，阿朴吗啡、卡麦角林、罗皮尼罗、普拉克索也有报道用于PD治疗。由于现有药物 主要以改善症状为目的，难以达到阻止或减少用药过程中多巴胺能神经元继续丢失，不能有 效改变病程进展，甚至有加速多巴胺能神经细胞丢失的毒副作用，如左旋多巴。
因此，开发出效果显著且副作用小的治疗相关中枢神经退行性疾病的新型药物是保障人们健康的迫切需要。
发明内容
本发明的目的在于提供一类多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂，其可通过抑制多巴胺转运蛋白和去甲肾上腺素转运蛋白的转运功能而上调突触间歇多巴胺和去甲肾上腺素的浓度，减少神经细胞死亡，从而可用于制备中枢神经退行性疾病的治疗药物。
在本发明的第一方面，提供了多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂的用途，用于制备治疗中枢神经退行性疾病的药物。
在本发明的另一优选例中，所述的多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂为一类补骨脂酚类化合物，其结构通式为：
其中，R1为氢、C1～C8的酰基或卤族。
R2、R3、R4、R5分别为氢或卤族。
上述C1～C8的酰基是指具有1～8个碳原子的支链或支链羧酸的酰基，例如甲酰基、乙酰基、丙酰基、异丙酰基、丁酰基、叔丁酰基、戊酰基、新戊酰基、己酰基、庚酰基和辛酰基支链羧酸的酰基(如丙二酸酰基)等。
上述的卤族是指氟、氯、溴或碘原子。优选氯原子。
本发明还涉及补骨脂酚类化合物的以酯、氨基甲酸酯或其他常规的“前体药物”的形式，当以这种形式给药时，在体内可转化成活性部分；
更优选地，上述补骨脂酚类化合物为13-羟基异补骨脂酚(在本文中也叫Bu)，其结构式如下：
或其衍生物。较佳的，上述补骨脂酚类化合物为1 3-羟基异补骨脂酚。
上述的13-羟基异补骨脂酚衍生物是指以13-羟基异补骨脂酚为先导化合物，对其进行进一步的结构修饰和改造，而得到对中枢神经退行性疾病具有疗效的化合物。
在本发明的另一优选例中，上述中枢神经退行性疾病包括：阿尔茨海默病(Alzheimerdisease，AD)、帕金森病(parkinson’s disease，PD)、亨廷顿病(Huntington disease，HD)、肌萎缩性脊髓侧索硬化症(amyotrophic lateral sclerosis，ALS)、Lewy体痴呆(dementia with lewy body，DLB)、多发梗死灶性痴呆(multi-infarct dementi2a，MID)、Pick小体病(Pick body disease)、大脑前叶退行性变(frontal lobe degeneration，FLD)、皮层基底节退行性变(corticobasal degeneration，CBD)、多系统萎缩症(multiple systematrophy，MSA)、渐进性上运动核瘫痪(progressive supranuclear palsy，PSP)、新变异型Creutzfeldt-Jakob病(new variant Creutzfeldt-Jakob diseas，nvCJD)。
更优选地，上述中枢神经退行性疾病为帕金森病(parkinson’s disease，PD)或阿尔茨海默病(Alzheimer disease，AD)。
在本发明的第二方面，提供了一类多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂的用途，用于制备治疗神经元细胞损伤或死亡相关的疾病的组合物，包括保健品和药物组合物，较佳的，是用于制备相关的药物组合物。
在本发明的第三方面，提供一种多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂剂的用途，用于制备治疗多巴胺和/或去甲肾上腺素功能低下性神经疾病的药物。
在本发明的第四方面，提供了多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂的用途，用于制备治疗中枢神经退行性疾病的药物组合物。
在本发明的第五方面，本发明还提供一种用于治疗中枢神经退行性疾病的药物组合物，所述药物组合物包含多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂及其药学上可接受的载体。上述药物的剂型是片剂、胶囊、可分散的粉末、颗粒剂、悬浮液、糖浆或注射剂等。
较佳的，上述多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂为一类结构通式为式I的补骨脂酚类化合物，其中，R1为氢、C1～C8的酰基或卤族；R2、R3、R4、R5分别为氢或卤族。
更佳的，上述多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂为结构式为式II的13-羟基异补骨脂酚或其衍生物。
另一方面，根据不同的需要，本发明的含多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂的组合物还可与其它治疗中枢神经退行性疾病的药物联合应用，来治疗中枢神经退行性疾病。本发明药物或药物组合物还可以用于治疗与神经元损伤或死亡相关的疾病。
本发明的其它方面由于本文的公开内容，对本领域的技术人员而言是显而易见的。
附图说明
图1：Bu对D8细胞毒性实验和对MPTP诱导D8细胞毒性反应的保护作用。
1：CHO细胞+1％DMSO的HBS；2：D8细胞+1％DMSO的HBS；3：D8细胞+33μMMPP+；4：D8细胞+33μM MPP++10μMGBR；5： D8细胞+33μM MPP++1μM Bu；6：D8细胞+33μM MPP++10μMBu；7：D8细胞+33μM MPP++100μM Bu；8：D8细胞+1μM Bu；9：D8细胞+10μM Bu；10：D8细胞+100μM Bu；
图2：转棒实验评价Bu对MPTP小鼠停留时间的影响。
D4、D9和D14，分别代表MPTP和药物处理后第四天、第九天和第十四天。
Solvent+NS：正常对照组；
Solvent+MPTP：代表PD模型组；
4mg/Kg+MPTP、20mg/Kg+MPTP和100mg/Kg+MPTP：分别代表Bu三个治疗剂量组；
LDP+MPTP：左旋多巴(100mg/Kg，ip)阳性对照组。
图3：转棒实验评价Bu处理14天后，对MPTP小鼠停留时间的影响。
说明见图2。
图4：TH免疫组织化学评价Bu对MPTP模型小鼠黑质多巴胺神经元的保护作用。
对照组(control)为正常小鼠，即100％；
MPTP/Vehicle：模型组；
4mg/Kg、20mg/Kg和100mg/Kg LDP，分别代表不同剂量组；
左旋多巴(LDP)：阳性对照组。
具体实施方式
如本文所用，所述的“本发明双重抑制剂”和“多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂”包括所有能同时完全地或部分地抑制多巴胺转运蛋白和去甲肾上腺素转运蛋白对多巴胺和去甲肾上腺素的摄取和转运功能的物质。
更优选的，本发明双重抑制剂为补骨脂酚类化合物以及它们的衍生物等。
在本发明的另一优选例中，所述的多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂为一类结构通式为式I的补骨脂酚类化合物，其中，R1为氢、C1～C8的酰基或卤族；R2、R3、R4、R5分别为氢或卤族。
上述C1～C8的酰基是指具有1～8个碳原子的支链或支链羧酸的酰基，例如甲酰基、乙酰基、丙酰基、异丙酰基、丁酰基、叔丁酰基、戊酰基、新戊酰基、己酰基、庚酰基、辛酰基或丙二酸酰基等。
上述的卤族是指氟、氯、溴或碘原子。优选氯原子。
本发明还涉及补骨脂酚类化合物的以酯、氨基甲酸酯或其他常规的“前体药物”的形式，当以这种形式给药时，在体内可转化成活性部分；
更优选地，所述的补骨脂酚类化合物为结构式为式II的13-羟基异补骨脂酚(在本文中也叫Bu)或其衍生物。
上述的13-羟基异补骨脂酚衍生物是指以13-羟基异补骨脂酚为先导化合物，对其进行进一步的结构修饰和改造，而得到对中枢神经退行性疾病具有疗效的化合物，包括本发明双重抑制剂在药学上可接受的盐。
本发明中，所述的多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂可以以纯净的补骨脂酚类化合物或其衍生物的形式存在；也可以以含有补骨脂酚类化合物或其衍生物的混合物或提取物(比如可提取自中药)的形式存在；或者，也可以以包含补骨脂酚类化合物或其衍生物的中药材或中药活性部位的形式存在。
发明人发现，本发明双重抑制剂能抑制多巴胺转运蛋白和去甲肾上腺素转运蛋白对多巴胺和去甲肾上腺素的摄取和转运功能作用，而对其它转运蛋白(如γ-氨基丁酸转运蛋白)无作用或作用不明显。这表明本发明双重抑制剂具有作用特异性。
本发明所述的中枢神经退行性疾病包括：阿尔茨海默病(Alzheimer disease，AD)、帕金森病(parkinson’s disease，PD)、亨廷顿病(Huntington disease，HD)、肌萎缩性脊髓侧索硬化症(amyotrophic lateral sclerosis，ALS)、Lewy体痴呆(dementia with lewy body，DLB)、多发梗死灶性痴呆(multi-infarct dementi2 a，MID)、Pick小体病(Pick body disease)、大脑前叶退行性变(frontal lobe degeneration，FLD)、皮层基底节退行性变(corticobasal degeneration，CBD)、多系统萎缩症(multiple system atrophy，MSA)、渐进性上运动核瘫痪(progressive supranuclearpalsy，PSP)、新变异型Creutzfeldt-Jakob病(new variant Creutzfeldt-Jakob disease，nvCJD)。
较佳地，所述的中枢神经退行性疾病为帕金森病(parkinson’s disease，PD)或阿尔茨海默病(Alzheimer disease，AD)。
本发明中，所述的多巴胺和或去甲肾上腺素功能低下性神经疾病是指由于神经突触间歇多巴胺和或去甲肾上腺素的浓度或含量病理性低下、活性低下而导致的神经系统疾病；或者由于神经突触间歇多巴胺和去甲肾上腺素的浓度或含量病理性低下、活性低下而导致的神经系统疾病。
在本发明的另一优选例中，所述的药物组合物含有：
补骨脂酚类化合物或其衍生物：5-10重量份；
药学上可接受的载体：80-150重量份；
其中，补骨脂酚类化合物或其衍生物的总含量为药物组合物总重量的0.01-99％，较佳地0.1-90％，更佳的0.1-20％。
在本发明的另一优选例中，所述的药物为13-羟基异补骨脂酚。13-羟基异补骨脂酚的总含量为本发明药物或药物组合物总重量的0.01-99％，较佳地0.1-90％，更佳的0.1-20％。
本发明双重抑制剂也可以由药学上或生理学可接受的酸或碱衍生的盐形式使用。这些盐包括(但不限于)与如下无机酸形成的盐：如盐酸、硫酸、硝酸、磷酸、以及与有机酸形成的盐，而有机酸则指乙酸、草酸、丁二酸、酒石酸、甲磺酸和马来酸。其他盐包括与碱金属或碱土金属(如钠、钾、钙或镁)形成的盐，以酯、氨基甲酸酯或其他常规的“前体药物”的形式(当以这种形式给药时，在体内可转化成活性部分)。
使用多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂在治疗中枢神经退行性疾病时，药物的量取决于疾病的性质和程度以及病人已接受治疗的情况。最终由处方医生决定给予病人多少剂量，临床使用的剂量为每公斤体重每日可使用0.05-300mg的多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂。
本发明还提供了一种含有本发明双重抑制剂的组合物，优选的，所述的组合物为药物组合物。一般，合适的含量是多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂占药物组合物总重量的0.01-99％，较佳地0.1-90％，更佳的0.1-20％。
除了作为活性成份的本发明双重抑制剂，所述的组合物中还可含有药学上可接受的载体，包括但不限于填充剂、崩解剂、润滑剂、助流剂、泡腾剂、矫味剂、包覆材料、膳食制品、或缓/控释剂等。根据不同的给药方式，所述的组合物可以制备成固体或凝胶等形式，如丸剂、片剂、胶囊、可分散的粉末、颗粒剂等；或者是液体形式，如注射剂、悬浮液、糖浆。它们适合口服给药、直肠给药、局部给药或肠胃外给药、或者静脉内给药等。
本发明中，“药学上可接受的”成分是适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应)即有合理的效益/风险比的物质。“药学上可接受的载体”是用于将本发明双重抑制剂传送给动物或人的药学上或食品上可接受的溶剂、悬浮剂或赋形剂。载体可以是液体或固体。
本发明的经口给药的固体组合物可采用片剂、丸剂、胶囊剂、散剂、颗粒剂、滴剂等形式。这些固体组合物中混合了1种或1种以上的活性物质和至少1种惰性稀释剂，例如，乳糖、甘露糖醇、葡萄糖、羟丙基纤维素、微晶纤维素、淀粉、聚乙烯毗咯烷酮、琼脂、果胶、硅铝酸镁、铝酸镁。还可按照常用方法使组合物中含有除了惰性稀释剂之外的添加剂，例如，硬脂酸镁等润滑剂、纤维素乙醇酸钙等崩解剂、乳糖等稳定剂、谷氨酸或天一氨酸等助溶剂。如是片剂或丸剂，还可根据需要，在其外部包裹上蔗糖、明胶、羟甲基纤维素、羟丙基甲基纤维索、邻苯二甲酸酯等糖衣或胃溶性、肠溶性薄膜。
经口给药的液体组合物包括药剂上允许的乳浊剂、溶液剂、悬浮剂、糖浆剂、酏剂等，通常使用的惰性稀释剂包括精制水、乙醇。该组合物中除了惰性稀释剂之外，还可包含湿润剂、悬浮剂等助剂，甜味剂、矫味剂、芳香剂和防腐剂。
非经口给药的注射剂包括无菌水性或非水性溶液剂、悬浮剂和乳浊剂。水性溶液剂和悬浮剂中包含注射剂用蒸馏水及生理盐水。非水溶性溶液剂和悬浮剂中包含两二醇，聚乙二醇，可可脂、橄揽油、蓖麻油等植物油，乙醇等醇类，阿拉伯胶、吐温80等。这些组合物中还可包含等渗剂、防腐剂、湿润剂、乳化剂、分散剂、稳定剂(例如，乳糖)、助溶剂(例如，谷氨酸、天冬氨酸)。用过滤除菌上述组合物，再配合使用灭菌剂就可达到无菌的目的。然后，利用上述组合物制得无菌的固体组合物，在使用前用水或无菌注射用溶剂溶解就可加以利用。
可用于配制本发明口服剂型的、具体的药学上可接受的载体和赋形剂例子，在美国专利No3,903,297(1975年9月2日授予Robert)中有描述。用于制造本发明的有用剂型的技术和组合物，在下列文献中有描述：7种现代制剂(7 Modern Pharmaceutics)第9和10章(Banker&Rhodes编辑，1979)：Lieberman等人，药物剂型：片剂(Pharmaceutical Dosage Forms：Tablets)(1981)；和Ansel，药物剂型导论(Introduction to Pharmaceutical Dosage Forms)2版(1976)。
本发明双重抑制剂，通过体外实验以及动物体内实验的研究证明，该类化合物能选择性抑制多巴胺转运蛋白、去甲肾上腺素转运蛋白，而对γ-氨基丁酸转运蛋白和五羟色胺转运蛋白活性均没有影响，并且该类化合物对细胞没有毒性；同样剂量下，本发明双重抑制剂药效显著好于目前临床帕金森病药物左旋多巴，并对黑质多巴胺神经元有明显地保护作用。因此，该类化合物将为临床治疗中枢神经退行性疾病提供新的药物选择，具有良好的市场前景。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室指南(New York：Cold Spring Harbor Laboratory Press，1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明中。
以下实施例中所用药品的来源如下：
13-羟基异补骨脂酚采用中国药检所市售产品；
1640培养基培养、小牛血清购自GIBCO公司；
3H-DA、3H-GABA、3H-五羟色胺、3H-去甲肾上腺素、购自Amersham Pharmacia Biotech公司；
安非他酮(标记为BRP)、GBR购自sigma；
左旋多巴购自Roche，上海；
中华仓鼠卵巢细胞(CHO)、COS-7细胞购自美国ATCC公司；
C57BL/6小鼠购自中科院动物中心。
其它化学试剂购自Sigma公司。
实施例1、体外筛选模型的建立
建立以五羟色胺、去甲肾上腺素、多巴胺、γ-氨基丁酸四种神经转运蛋白(5-HTT、NET、DAT、GAT-1)为靶标的活性筛选细胞系的建立。通过将大鼠的5-HTT、NET、DAT、GAT-1全长编码序列(5-HTT的GenBank登录号为GI207086；NET的GenBank登录号为GI4630791；DAT的GenBank登录号为GI310097；GAT-1的GenBank登录号为GI204221)克隆于pCDNA3载体(美国invitrogen公司)的多克隆位点中，用电穿孔方法转染导入中华仓鼠卵巢细胞(CHO)，48小时后用含G418的1640培养基培养。10天后对照组细胞全部死亡，而实验组形成许多细胞克隆。挑取克隆培养一周后，待细胞铺满孔底，吸去培养基，同上用胰酶消化。每孔中的细胞分别接种于两块96孔平板的相应的孔中。待细胞长满孔底后，其中一块板用于同位素流量测定。将对应的另一块板中转运活性高的孔中的细胞逐级扩大培养，每一级都进行同位素流量测定后选取转运活力较高细胞株培养，最后选取转运活力最高的细胞克隆(分别命名为D8，G1细胞)保种，建立永久表达五羟色胺、去甲肾上腺素、多巴胺、γ-氨基丁酸的多种神经转运蛋白的CHO细胞系(分别命名为：S6，N1，D8，GAT-1)。
实施例2、多巴胺转运蛋白激动剂体外筛选及选择专一性的测定
培养D8细胞于48孔板(Costar)至平板铺满(大约每孔6万细胞)。弃培液。用PBS洗涤一次，吸去PBS溶液，每孔加入90ul HBS(10mM Hepes，100mM NaCl，PH8.0)，25℃温育10分钟，每孔加入10ul HBS反应液。实验组及阳性对照药加入80ul HBS，10ul不同浓度的药物，及10ul 3H-DA(Amersham Pharmacia Biotech)，100μM维生素C和100μM帕吉林。25℃温育20分钟，用冰浴的PBS溶液洗涤三遍，用裂解液裂解60分钟，吸取各孔的裂解液加入到1.2ml的闪烁液中，放入液闪计数仪(Beckman LS 5000TA)中检测同位素的含量(DMP值)，以此来衡量药物对多巴胺转运蛋白的转运活性的影响。
药物对于GABA转运蛋白活性检测，方法类似于多巴胺转运蛋白，用GAT-1细胞替代D8细胞，50nM3H-GABA(Amersham Pharmacia Biotech)取代了反应体系中的3H-DA，其他方法不变。
药物对于五羟色胺转运蛋白活性检测，方法类似于多巴胺转运蛋白，用S6细胞替代D8细胞，50nM3H-五羟色胺取代了反应体系中的3H-DA，其他方法不变。
药物对于去甲肾上腺素转运蛋白活性检测，方法类似于多巴胺转运蛋白，用N1细胞替代D8细胞，50nM3H-去甲肾上腺素取代了反应体系中的3H-DA，其他方法不变。
结果见表一：
表一：13-羟基异补骨脂酚对单胺类神经递质转运蛋白的抑制作用
从表一可知：在0.3μM-10μM浓度下，13-羟基异补骨脂酚(Bu)对多巴胺转运蛋白(DAT)也显示很强的抑制活力(P＜0.05)。在0.3uM浓度下可抑制37％，1μM浓度下可抑制60％，10uM浓度下可抑制88％。在0.3μM-10μM浓度下，Bu对D8细胞多巴胺摄取活力的抑制效果与阳性对照药物安非他酮(BPR)相当(P＞0.05)。
在0.1μM-10μM浓度下，Bu对去甲肾上腺素转运蛋白的摄取活力有显著抑制作用(P＜0.05)。0.3μM浓度下可抑制36％，1μM浓度下可抑制60％，10μM浓度下可抑制87.8％。在1μM浓度下，Bu对NET细胞摄取活力的抑制效果与阳性对照药物安非他酮(BPR)相当(P＞0.05)。
在0.3μM-10μM浓度下，Bu对GAT-1细胞的γ-氨基丁酸转运蛋白和S6细胞的5-羟色胺转运蛋白的活性均没有影响(P＞0.05)。
上述结果表明13-羟基异补骨脂酚(Bu)对多巴胺转运蛋白和去甲肾上腺素转运蛋白均有抑制活性，抑制作用强于阳性对照药物安非他酮(BPR)，而对γ-氨基丁酸转运蛋白和5-羟色胺转运蛋白的活性均没有影响。因此，13-羟基异补骨脂酚对多巴胺转运蛋白和去甲肾上腺素转运蛋白的抑制作用具有选择性和特异性。
实施例3 13-羟基异补骨脂酚细胞毒性实验及对MPP+细胞毒的抑制作用
将D8细胞于1640培养基培养，加10％小牛血清培养，待长满培养皿后，胰酶消化，接种于48孔细胞板中，继续培养待细胞数量达到105左右，分别处理如下：换液后，对照组加10μl对照液(含1％DMSO的HBS)，药物不同剂量组分别加10μl不同浓度的Bu，使其终浓度分别为1μM，10μM和100μM；另外，以33μM MPP+单独处理和与上述不同浓度Bu共同处理细胞；细胞继续培养24小时，在第20小时加MTT，使终浓度为0.5mg/ml。反应结束后，吸去培养液，加100％DMSO，37℃温育10分钟。转移至96孔板，在570nm波长下用酶标检测仪测每个孔OD值。
结果见图1：在分别含有100μM、10μM和1μMBu的1640培养液环境下，经24小时培养的D8细胞的生长能力与对照组细胞无显著性差异，表明100μM以内Bu无细胞毒性作用。33μM MPP+作用于D8细胞，可使细胞活力抑制75％，Bu呈浓度依赖性地缓解这种抑制作用，表明Bu有保护MPP+诱导的D8细胞免受损伤的作用。
实施例4 13-羟基异补骨脂酚对帕金森病大鼠模型的治疗作用
1.行为学检测
动物及分组：C57BL/6小鼠，雄性，13月龄，体重28-36g，共60只，购于中国科学院上海实验动物中心，SPF级。常规饲养，光照时间7AM-7PM。正式实验前，对动物进行转棒爬行训练。训练方法：将动物放在转棒测试仪(DigBehav-RRTM，上海吉量科技有限公司)上，根据小鼠活动能力，设定转速区间为8-17转/分钟，时间为5.5分钟；每天训练3次，共训练14天，软件自动记录小鼠在转棒停留时间(Retentative Time)。根据停留时间筛选动物，将小于240秒的动物剔除。将符合标准动物随机分为6组，即正常组、模型组、低剂量组、中剂量组、高剂量组及左旋多巴对照组，每组9只。分组后，经统计学分析，各组小鼠滚筒爬行时间以及体重没有显著性差异。
动物处理：模型组、低剂量组、中剂量组、高剂量组及左旋多巴对照组分别给予空白溶剂、4mg/Kg Bu、20mg/Kg Bu、100mg/Kg Bu及左旋多巴(Roche，上海)100mg/Kg(含25mg/Kg苄丝肼)，腹腔注射；半小时后，分别予以MPTP(Sigma，USA)20mg/Kg颈皮下注射。正常组，用等体积空白溶剂和0.9％生理盐水分别代替观察药物和MPTP溶液。共处理14天。
观察指标：于处理后第4天、第9天、第14天观察动物滚筒停留时间，每次观察时间点为1h、2h、4h、6h、8h、10h、24h后，检测参数设定同训练参数。
结果见图2，第4天MPTP处理4小时后，Bu高剂量组可轻度改善MPTP对动物运动的影响。第9天、14天，中高剂量组均可明显改善动物运动减少症状，而第14天改善作用明显强于第4天和第9天，。
第14天分别测定MPTP 1小时、2小时、4小时、6小时、8小时和10小时后行为学的检测，动物在MPTP注射4小时后Bu治疗作用显著，其中第6小时作用最为明显，并且呈现剂量依赖效应，见图3。
结论：Bu对PD模型行为学异常有改善作用，提示BU对帕金森氏病具有治疗作用。
2.形态学检测
第15天给药6小时后，将所有动物处死，多聚甲醛灌注固定，快速取脑组织，用免疫组织化学检测黑质TH阳性神经元：4℃下，将标本用多聚甲醛3ml固定24小时，然后将组织置入10ml蔗糖PBS缓冲液中。冰冻切片机，连续切片，厚度40μm.将切片放入含3％羊血清和0.2％TritonX-100的PB液孵育过夜。4℃下，加兔抗TH血清孵育48小时。用0.01M PBS洗3-4次，每次5分钟，然后将切片放入含二抗(生物素标记羊抗兔IgG)37℃孵育温育1.5小时。PBS洗三次后，入ABC液中37℃温育1小时。然后用0.05M Tris缓冲液洗1次。加入含DAB和H2O2的0.05M Tris缓冲液中显色。
结果：酪氨酸羟化酶(TH)是多巴胺神经元特异性标记物。本研究通过免疫组织化学技术染色观察到MPTP小鼠黑质TH阳性神经元数目是正常动物的40％，符合PD病理学特征。于第15天药物和MPTP处理后6小时，Bu三个剂量组黑质区TH免疫阳性细胞数明显高于单独MPTP处理动物组，见图4。
结论：Bu对PD模型小鼠的黑质多巴能神经有明显保护作用。
实施例5 13-羟基异补骨脂酚片剂的制备
取100g 13-羟基异补骨脂酚、560g微晶纤维素、380g无水乳糖、200g硬脂酸镁、30g氧化硅，取上述配方中除硬脂酸镁外所有成分混合25-30分钟，再筛入硬脂酸镁，继续混匀，然后冲压成片。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (3)
1.多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂在制备治疗中枢神经退行性疾病的药物中的应用，其特征在于，所述的中枢神经退行性疾病为阿尔茨海默病或帕金森病；所述的多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂为式II所示的13-羟基异补骨脂酚或其药学上或生理学可接受的酸或碱衍生的盐：
2.如权利要求1所述的用途，其特征在于，所述药物的剂型是片剂、胶囊、可分散的粉末、颗粒剂、悬浮液、糖浆、酏剂或注射剂。
3.如权利要求1所述的用途，其特征在于，所述的多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂为13-羟基异补骨脂酚。
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100366018A CN101224201B (zh) | 2007-01-18 | 2007-01-18 | 多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂的应用 |
| PCT/CN2008/000132 WO2008089659A1 (en) | 2007-01-18 | 2008-01-18 | The use of dopamine transporters and noradrenaline transporters dual inhibitors |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100366018A CN101224201B (zh) | 2007-01-18 | 2007-01-18 | 多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂的应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101224201A CN101224201A (zh) | 2008-07-23 |
| CN101224201B true CN101224201B (zh) | 2011-10-05 |
Family
ID=39644110
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2007100366018A Expired - Fee Related CN101224201B (zh) | 2007-01-18 | 2007-01-18 | 多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂的应用 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101224201B (zh) |
| WO (1) | WO2008089659A1 (zh) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006122160A2 (en) * | 2005-05-09 | 2006-11-16 | Unigen Pharmaceuticals, Inc. | Compositions of bakuchiol and methods of making the same |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI347183B (en) * | 2003-12-23 | 2011-08-21 | Lundbeck & Co As H | 2-(1h-indolylsulfanyl)-benzyl amine derivatives |
| JP2006028161A (ja) * | 2004-06-15 | 2006-02-02 | Taisho Pharmaceut Co Ltd | ホコツシ配合モノアミン再取り込み阻害剤 |
| CN101088498B (zh) * | 2006-06-13 | 2011-09-07 | 和泓生物技术（上海）有限公司 | 补骨脂酚类化合物的应用 |
-
2007
- 2007-01-18 CN CN2007100366018A patent/CN101224201B/zh not_active Expired - Fee Related
-
2008
- 2008-01-18 WO PCT/CN2008/000132 patent/WO2008089659A1/zh active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006122160A2 (en) * | 2005-05-09 | 2006-11-16 | Unigen Pharmaceuticals, Inc. | Compositions of bakuchiol and methods of making the same |
Non-Patent Citations (4)
| Title |
|---|
| 刘国卿.药理学 第1版.北京：中国医药科技出版社,2000,129,133. |
| 刘国卿.药理学 第1版.北京:中国医药科技出版社,2000,129,133. * |
| 补骨脂中1种单萜对线粒体脂质过氧化的抑制作用[英]/Haraguchi H…//Planta Med.-2000,66(6).-569-571.国外医学中医中药分册第23卷 第5期.2001,第23卷(第5期),295-296. |
| 补骨脂中1种单萜对线粒体脂质过氧化的抑制作用[英]/Haraguchi H…//Planta Med.-2000,66(6).-569-571.国外医学中医中药分册第23卷 第5期.2001,第23卷(第5期),295-296. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101224201A (zh) | 2008-07-23 |
| WO2008089659A1 (en) | 2008-07-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Ha et al. | Huperzine a as potential treatment of Alzheimer's disease: an assessment on chemistry, pharmacology, and clinical studies | |
| US5151419A (en) | Composition for the treatment of schizophrenia | |
| CN107820425A (zh) | 用于治疗神经肌肉病症的化合物 | |
| UA119445C2 (uk) | Нові композиції для лікування неврологічних розладів | |
| WO2008000142A1 (fr) | Agoniste du transporteur de la dopamine et ses utilisations | |
| CN110300581B (zh) | 具有奇数碳的脂类化合物及其作为医药组合物或者营养补充剂的用途 | |
| WO2007038610A2 (en) | Use of natural products for treatment of neurological disorders | |
| TW201036949A (en) | Treatment of dyskinesia related disorders | |
| US10603270B2 (en) | Skin care compositions and methods of use thereof | |
| Hotchandani et al. | Heterocyclic Amaryllidaceae alkaloids: biosynthesis and pharmacological applications | |
| CN110167574A (zh) | 包含芫花树花提取物或其分离物作为有效成分的神经退行性疾病预防或者治疗用药学组合物 | |
| US20110207830A1 (en) | Composition for treating or preventing amyloid-related diseases comprising 4-o-methylhonokiol | |
| EP3074414B1 (en) | Withanolides useful for the treatment of neurodegenerative diseases | |
| Zhang et al. | Synthesis and evaluation of andrographolide derivatives as potent anti-osteoporosis agents in vitro and in vivo | |
| KR101208198B1 (ko) | Ｌｒｒｋ２ 인산화효소 억제 활성을 갖는 화합물을 유효성분으로 함유하는 파킨슨병 치료 또는 예방용 약학조성물 | |
| US20100227851A1 (en) | Method of preventing and/or treating a neurodegenerative disease by administering an extract of Lycoris chejuensis and/or a compound isolated therefrom | |
| CN101224201B (zh) | 多巴胺转运蛋白和去甲肾上腺素转运蛋白双重抑制剂的应用 | |
| CN101342173A (zh) | 洛贝林在制备治疗神经元凋亡疾病的药物中的应用 | |
| Rahman et al. | Antinociceptive and anti-inflammatory effect of Crinum asiaticum bulb extract | |
| WO2019175873A1 (en) | Compounds and uses for the treatment and prevention of diseases and conditions associate with or aggravated by impared mitophagy | |
| US20130136811A1 (en) | Compositions and Methods for Pain Reduction | |
| JP7295145B2 (ja) | 神経変性疾患を治療するための医薬及びその使用 | |
| US20210220340A1 (en) | Composition for prevention or treatment of neurodegenerative disease | |
| Manjusha et al. | Antiparkinsonian activity of Moringa concanensis and Sesbania grandiflora in 6-Hydroxy dopamine induced parkinsonism in rats | |
| Bopaiah et al. | Pharmacological study on antidepressant activity of 50% ethanol extract of a formulated ayurvedic product in rats |
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 | ||
| ASS | Succession or assignment of patent right |
Owner name: SINO-AMERICAN GUOLIAN (SHANGHAI) BIOTECHNOLOGY RES Free format text: FORMER OWNER: HEHONG BIO-TECH (SHANGHAI) CO., LTD. Effective date: 20120220 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 201203 PUDONG NEW AREA, SHANGHAI TO: 200333 PUTUO, SHANGHAI |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20120220 Address after: 200333, room 2, building 879, Lane 307, Zhongjiang Road, Shanghai, Putuo District Patentee after: Guolian (Shanghai) Biotechnology Research Co., Ltd. Address before: 201203 Curie Road, Zhangjiang hi tech park, Shanghai, Pudong New Area, No. 1 Patentee before: Hehong Biotechnology (Shanghai) Co., Ltd. |
|
| C56 | Change in the name or address of the patentee |
Owner name: SHANGHAI UNITED STEM CELL TECHNOLOGY CO., LTD. Free format text: FORMER NAME: ZHONGMEI GUOLIAN (SHANGHAI) BIOTECHNOLOGY RESEARCH CO., LTD. |
|
| CP01 | Change in the name or title of a patent holder |
Address after: 200333, room 2, building 879, Lane 307, Zhongjiang Road, Shanghai, Putuo District Patentee after: Shanghai United Stem Cell Technology Co., Ltd. Address before: 200333, room 2, building 879, Lane 307, Zhongjiang Road, Shanghai, Putuo District Patentee before: Guolian (Shanghai) Biotechnology Research Co., Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20111005 Termination date: 20170118 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |