JP7179739B2 - 医学的治療における使用のための3-β-ヒドロキシ-5-α-プレグナン-20-オン - Google Patents
医学的治療における使用のための3-β-ヒドロキシ-5-α-プレグナン-20-オン Download PDFInfo
- Publication number
- JP7179739B2 JP7179739B2 JP2019540059A JP2019540059A JP7179739B2 JP 7179739 B2 JP7179739 B2 JP 7179739B2 JP 2019540059 A JP2019540059 A JP 2019540059A JP 2019540059 A JP2019540059 A JP 2019540059A JP 7179739 B2 JP7179739 B2 JP 7179739B2
- Authority
- JP
- Japan
- Prior art keywords
- gaba
- hydroxy
- pregnan
- receptor
- receptors
- 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.)
- Active
Links
- AURFZBICLPNKBZ-FZCSVUEKSA-N 3beta-hydroxy-5alpha-pregnan-20-one Chemical compound C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1 AURFZBICLPNKBZ-FZCSVUEKSA-N 0.000 title claims description 69
- 238000013160 medical therapy Methods 0.000 title 1
- 208000000323 Tourette Syndrome Diseases 0.000 claims description 34
- 208000016620 Tourette disease Diseases 0.000 claims description 34
- -1 ecitalopram Chemical compound 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 11
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 7
- 229960004039 finasteride Drugs 0.000 claims description 6
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 claims description 6
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 claims description 5
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 claims description 5
- GDLIGKIOYRNHDA-UHFFFAOYSA-N Clomipramine Chemical compound C1CC2=CC=C(Cl)C=C2N(CCCN(C)C)C2=CC=CC=C21 GDLIGKIOYRNHDA-UHFFFAOYSA-N 0.000 claims description 5
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 claims description 5
- PLDUPXSUYLZYBN-UHFFFAOYSA-N Fluphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 PLDUPXSUYLZYBN-UHFFFAOYSA-N 0.000 claims description 5
- INJOMKTZOLKMBF-UHFFFAOYSA-N Guanfacine Chemical compound NC(=N)NC(=O)CC1=C(Cl)C=CC=C1Cl INJOMKTZOLKMBF-UHFFFAOYSA-N 0.000 claims description 5
- 229940030600 antihypertensive agent Drugs 0.000 claims description 5
- 239000002220 antihypertensive agent Substances 0.000 claims description 5
- 239000003693 atypical antipsychotic agent Substances 0.000 claims description 5
- 229960001653 citalopram Drugs 0.000 claims description 5
- 229960004606 clomipramine Drugs 0.000 claims description 5
- 229960002896 clonidine Drugs 0.000 claims description 5
- 229960004199 dutasteride Drugs 0.000 claims description 5
- JWJOTENAMICLJG-QWBYCMEYSA-N dutasteride Chemical compound O=C([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)N[C@@H]4CC3)C)CC[C@@]21C)NC1=CC(C(F)(F)F)=CC=C1C(F)(F)F JWJOTENAMICLJG-QWBYCMEYSA-N 0.000 claims description 5
- 229960002464 fluoxetine Drugs 0.000 claims description 5
- 229960002690 fluphenazine Drugs 0.000 claims description 5
- 229960004038 fluvoxamine Drugs 0.000 claims description 5
- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 claims description 5
- 229960002048 guanfacine Drugs 0.000 claims description 5
- 229960003878 haloperidol Drugs 0.000 claims description 5
- YVUQSNJEYSNKRX-UHFFFAOYSA-N pimozide Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCN1CCC(N2C(NC3=CC=CC=C32)=O)CC1 YVUQSNJEYSNKRX-UHFFFAOYSA-N 0.000 claims description 5
- 229960003634 pimozide Drugs 0.000 claims description 5
- 239000003772 serotonin uptake inhibitor Substances 0.000 claims description 5
- 229960002073 sertraline Drugs 0.000 claims description 5
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 claims description 5
- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 claims description 5
- 229960000607 ziprasidone Drugs 0.000 claims description 5
- 229940123445 Tricyclic antidepressant Drugs 0.000 claims description 4
- 239000003887 narcotic antagonist Substances 0.000 claims description 4
- 239000003029 tricyclic antidepressant agent Substances 0.000 claims description 4
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 361
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 181
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 181
- 102000005962 receptors Human genes 0.000 description 118
- 108020003175 receptors Proteins 0.000 description 118
- 230000000694 effects Effects 0.000 description 84
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 50
- 208000035475 disorder Diseases 0.000 description 49
- 150000003431 steroids Chemical class 0.000 description 46
- 208000001613 Gambling Diseases 0.000 description 37
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 33
- CYKYBWRSLLXBOW-GDYGHMJCSA-N 5-alpha-THDOC Chemical compound C1[C@H](O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CC[C@H]21 CYKYBWRSLLXBOW-GDYGHMJCSA-N 0.000 description 29
- 230000004044 response Effects 0.000 description 26
- 238000011282 treatment Methods 0.000 description 26
- 210000004027 cell Anatomy 0.000 description 22
- CBMYJHIOYJEBSB-YSZCXEEOSA-N 5alpha-androstane-3beta,17beta-diol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 CBMYJHIOYJEBSB-YSZCXEEOSA-N 0.000 description 21
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 16
- 230000009471 action Effects 0.000 description 15
- 230000001404 mediated effect Effects 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- 230000001052 transient effect Effects 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- 239000003814 drug Substances 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 9
- 230000001965 increasing effect Effects 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- 239000002858 neurotransmitter agent Substances 0.000 description 9
- 208000024891 symptom Diseases 0.000 description 9
- 210000004556 brain Anatomy 0.000 description 8
- 230000001419 dependent effect Effects 0.000 description 8
- 229960003638 dopamine Drugs 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 239000005557 antagonist Substances 0.000 description 7
- 208000015114 central nervous system disease Diseases 0.000 description 7
- 206010012335 Dependence Diseases 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 101100244562 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) oprD gene Proteins 0.000 description 6
- 108700023159 delta Opioid Receptors Proteins 0.000 description 6
- 102000048124 delta Opioid Receptors Human genes 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 229960002200 flunitrazepam Drugs 0.000 description 6
- 230000003389 potentiating effect Effects 0.000 description 6
- 230000035882 stress Effects 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- PPTYJKAXVCCBDU-UHFFFAOYSA-N Rohypnol Chemical compound N=1CC(=O)N(C)C2=CC=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1F PPTYJKAXVCCBDU-UHFFFAOYSA-N 0.000 description 5
- 208000008234 Tics Diseases 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 239000003098 androgen Substances 0.000 description 5
- 230000000903 blocking effect Effects 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 230000002085 persistent effect Effects 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 230000011664 signaling Effects 0.000 description 5
- 206010034158 Pathological gambling Diseases 0.000 description 4
- AURFZBICLPNKBZ-UHFFFAOYSA-N Pregnanolone Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(=O)C)C1(C)CC2 AURFZBICLPNKBZ-UHFFFAOYSA-N 0.000 description 4
- 230000001548 androgenic effect Effects 0.000 description 4
- 210000003169 central nervous system Anatomy 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 230000008482 dysregulation Effects 0.000 description 4
- 230000003371 gabaergic effect Effects 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 230000000670 limiting effect Effects 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 229940126570 serotonin reuptake inhibitor Drugs 0.000 description 4
- 230000002459 sustained effect Effects 0.000 description 4
- YPEARZUTWVZHIZ-SRJHXTLLSA-N 1-[(8r,9s,10s,13s,14s,17s)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]ethanol Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(O)C)[C@@]1(C)CC2 YPEARZUTWVZHIZ-SRJHXTLLSA-N 0.000 description 3
- VTBHBNXGFPTBJL-UHFFFAOYSA-N 4-tert-butyl-1-sulfanylidene-2,6,7-trioxa-1$l^{5}-phosphabicyclo[2.2.2]octane Chemical compound C1OP2(=S)OCC1(C(C)(C)C)CO2 VTBHBNXGFPTBJL-UHFFFAOYSA-N 0.000 description 3
- QZLYKIGBANMMBK-UGCZWRCOSA-N 5α-Androstane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CCC[C@@]2(C)CC1 QZLYKIGBANMMBK-UGCZWRCOSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- 229940049706 benzodiazepine Drugs 0.000 description 3
- 208000030499 combat disease Diseases 0.000 description 3
- 239000003163 gonadal steroid hormone Substances 0.000 description 3
- 230000003054 hormonal effect Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 230000001537 neural effect Effects 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 230000004962 physiological condition Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 210000001103 thalamus Anatomy 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VZRAKVPDZIQRGT-WZBAXQLOSA-N (8r,9s,10s,13r,14s,17r)-17-ethenyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthrene Chemical compound C1CCC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)C=C)[C@@H]4[C@@H]3CCC21 VZRAKVPDZIQRGT-WZBAXQLOSA-N 0.000 description 2
- JWMFYGXQPXQEEM-NUNROCCHSA-N 5β-pregnane Chemical compound C([C@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](CC)[C@@]2(C)CC1 JWMFYGXQPXQEEM-NUNROCCHSA-N 0.000 description 2
- 108010066551 Cholestenone 5 alpha-Reductase Proteins 0.000 description 2
- 206010010219 Compulsions Diseases 0.000 description 2
- 206010013142 Disinhibition Diseases 0.000 description 2
- 102000005915 GABA Receptors Human genes 0.000 description 2
- 108010005551 GABA Receptors Proteins 0.000 description 2
- 102000004300 GABA-A Receptors Human genes 0.000 description 2
- 108090000839 GABA-A Receptors Proteins 0.000 description 2
- 208000030990 Impulse-control disease Diseases 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
- 208000013716 Motor tics Diseases 0.000 description 2
- 241000209094 Oryza Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- ORNBQBCIOKFOEO-YQUGOWONSA-N Pregnenolone Natural products O=C(C)[C@@H]1[C@@]2(C)[C@H]([C@H]3[C@@H]([C@]4(C)C(=CC3)C[C@@H](O)CC4)CC2)CC1 ORNBQBCIOKFOEO-YQUGOWONSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 210000003050 axon Anatomy 0.000 description 2
- 230000003542 behavioural effect Effects 0.000 description 2
- 150000001557 benzodiazepines Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 230000002964 excitative effect Effects 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- 210000001320 hippocampus Anatomy 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000001577 neostriatum Anatomy 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 230000007310 pathophysiology Effects 0.000 description 2
- 239000008177 pharmaceutical agent Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 150000003128 pregnanes Chemical class 0.000 description 2
- 229960000249 pregnenolone Drugs 0.000 description 2
- ORNBQBCIOKFOEO-QGVNFLHTSA-N pregnenolone Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 ORNBQBCIOKFOEO-QGVNFLHTSA-N 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 230000010346 psychosocial stress Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 239000012896 selective serotonin reuptake inhibitor Substances 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
- 230000000638 stimulation Effects 0.000 description 2
- 239000002438 stress hormone Substances 0.000 description 2
- 210000000225 synapse Anatomy 0.000 description 2
- 230000000946 synaptic effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000001256 tonic effect Effects 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 230000001755 vocal effect Effects 0.000 description 2
- CEBZORSAHLSRQW-AHUZIMQLSA-N (3r,8s,9s,10s,13r,14s,17s)-17-ethyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-ol Chemical compound C1CC2C[C@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](CC)[C@@]1(C)CC2 CEBZORSAHLSRQW-AHUZIMQLSA-N 0.000 description 1
- RAJWOBJTTGJROA-UHFFFAOYSA-N (5alpha)-androstane-3,17-dione Natural products C1C(=O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC21 RAJWOBJTTGJROA-UHFFFAOYSA-N 0.000 description 1
- MQJKLMCFKPSRHH-MSFXPVEOSA-N (8R,9S,10S,13R,14S,17S)-17-ethyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-15-ol Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C(O)C[C@H](CC)[C@@]1(C)CC2 MQJKLMCFKPSRHH-MSFXPVEOSA-N 0.000 description 1
- YJDYCULVYZDESB-HQEMIIEJSA-N (8r,9s,10s,13s,14s)-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,14,15,16-tetradecahydrocyclopenta[a]phenanthren-17-one Chemical compound C1CCC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC21 YJDYCULVYZDESB-HQEMIIEJSA-N 0.000 description 1
- RSRDWHPVTMQUGZ-QYYVTAPASA-N 1-[(5r,8r,9s,10s,13s,14s,17s)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]ethanone Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1 RSRDWHPVTMQUGZ-QYYVTAPASA-N 0.000 description 1
- RSRDWHPVTMQUGZ-OZIWPBGVSA-N 1-[(8r,9s,10s,13s,14s,17s)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]ethanone Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RSRDWHPVTMQUGZ-OZIWPBGVSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- ZESRJSPZRDMNHY-YFWFAHHUSA-N 11-deoxycorticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 ZESRJSPZRDMNHY-YFWFAHHUSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- 239000003148 4 aminobutyric acid receptor blocking agent Substances 0.000 description 1
- 239000003477 4 aminobutyric acid receptor stimulating agent Substances 0.000 description 1
- QUKZBUCPOSYYFO-KYQPOWKGSA-N 5alpha-Androstan-17beta-ol Chemical compound C1CCC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 QUKZBUCPOSYYFO-KYQPOWKGSA-N 0.000 description 1
- RAJWOBJTTGJROA-WZNAKSSCSA-N 5alpha-androstane-3,17-dione Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC[C@H]21 RAJWOBJTTGJROA-WZNAKSSCSA-N 0.000 description 1
- JWMFYGXQPXQEEM-GCOKGBOCSA-N 5α-pregnane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](CC)[C@@]2(C)CC1 JWMFYGXQPXQEEM-GCOKGBOCSA-N 0.000 description 1
- 241000238876 Acari Species 0.000 description 1
- 206010001488 Aggression Diseases 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- FMGSKLZLMKYGDP-UHFFFAOYSA-N Dehydroepiandrosterone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CC=C21 FMGSKLZLMKYGDP-UHFFFAOYSA-N 0.000 description 1
- 208000026331 Disruptive, Impulse Control, and Conduct disease Diseases 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- GRRNUXAQVGOGFE-UHFFFAOYSA-N Hygromycin-B Natural products OC1C(NC)CC(N)C(O)C1OC1C2OC3(C(C(O)C(O)C(C(N)CO)O3)O)OC2C(O)C(CO)O1 GRRNUXAQVGOGFE-UHFFFAOYSA-N 0.000 description 1
- 208000015592 Involuntary movements Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 208000029726 Neurodevelopmental disease Diseases 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- 208000023655 Tic Diseases 0.000 description 1
- 108010084455 Zeocin Proteins 0.000 description 1
- 230000007488 abnormal function Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 208000012761 aggressive behavior Diseases 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- 210000004727 amygdala Anatomy 0.000 description 1
- 230000001195 anabolic effect Effects 0.000 description 1
- 239000003936 androgen receptor antagonist Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 150000001441 androstanes Chemical class 0.000 description 1
- 150000001443 androstenes Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- 210000004227 basal ganglia Anatomy 0.000 description 1
- 208000013404 behavioral symptom Diseases 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 239000002981 blocking agent Substances 0.000 description 1
- 239000005388 borosilicate glass Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000002060 circadian Effects 0.000 description 1
- 238000009225 cognitive behavioral therapy Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000003179 convulsant agent Substances 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 238000009223 counseling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- ZESRJSPZRDMNHY-UHFFFAOYSA-N de-oxy corticosterone Natural products O=C1CCC2(C)C3CCC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 ZESRJSPZRDMNHY-UHFFFAOYSA-N 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 description 1
- 229940119740 deoxycorticosterone Drugs 0.000 description 1
- 238000000586 desensitisation Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 230000007831 electrophysiology Effects 0.000 description 1
- 238000002001 electrophysiology Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229960004341 escitalopram Drugs 0.000 description 1
- WSEQXVZVJXJVFP-FQEVSTJZSA-N escitalopram Chemical compound C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-FQEVSTJZSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000012173 estrus Effects 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 210000004326 gyrus cinguli Anatomy 0.000 description 1
- 231100000508 hormonal effect Toxicity 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- GRRNUXAQVGOGFE-NZSRVPFOSA-N hygromycin B Chemical compound O[C@@H]1[C@@H](NC)C[C@@H](N)[C@H](O)[C@H]1O[C@H]1[C@H]2O[C@@]3([C@@H]([C@@H](O)[C@@H](O)[C@@H](C(N)CO)O3)O)O[C@H]2[C@@H](O)[C@@H](CO)O1 GRRNUXAQVGOGFE-NZSRVPFOSA-N 0.000 description 1
- 229940097277 hygromycin b Drugs 0.000 description 1
- 238000003365 immunocytochemistry Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000002977 intracellular fluid Anatomy 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 230000029849 luteinization Effects 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 230000017311 musculoskeletal movement, spinal reflex action Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 230000007372 neural signaling Effects 0.000 description 1
- 238000002610 neuroimaging Methods 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 210000001328 optic nerve Anatomy 0.000 description 1
- 230000002450 orbitofrontal effect Effects 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000027758 ovulation cycle Effects 0.000 description 1
- 238000012402 patch clamp technique Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- CWCMIVBLVUHDHK-ZSNHEYEWSA-N phleomycin D1 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC[C@@H](N=1)C=1SC=C(N=1)C(=O)NCCCCNC(N)=N)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C CWCMIVBLVUHDHK-ZSNHEYEWSA-N 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229960002847 prasterone Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 210000002442 prefrontal cortex Anatomy 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 150000003146 progesterones Chemical class 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000007428 synaptic transmission, GABAergic Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 230000024664 tolerance induction Effects 0.000 description 1
- 230000009478 tonic inhibition Effects 0.000 description 1
- 238000012301 transgenic model Methods 0.000 description 1
- 238000005406 washing Methods 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- 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
- A61K31/13—Amines
- A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
-
- 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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
Description
ヒトα1、β、γGABAA受容体サブタイプおよびα4、β、δGABAA受容体サブタイプに対する3β-ヒドロキシ-5α-プレグナン-20-オンのGABAA受容体効果の試験のためのアッセイ。
2)GABAA受容体正の調節ステロイド(テトラヒドロデオキシコルチコステロン(THDOC)および3α-ヒドロキシ-5α-アンドロスタン-17-オール(3α-OH-アジオール))の非存在および存在下において、Dynaflow(商標)系による、HEK-293細胞に対する、3β-ヒドロキシ-5α-プレグナン-20-オンの効果を調査すること。これらの試験において、プロトコールを、シナプス間隙における生理学的条件に類似するように至適化させた。
GABA適用:Dynaflow機器の使用によって、ほとんど生理学的条件の間にトランスフェクションしたHEK-293を研究することは可能であった。Dynaflowシステムは、時間で40ミリ秒程から数分間までの間の溶液の適用を可能にした。生理学的に、シナプス間隙中で、GABAは約2ミリ秒間でmM範囲で放出された。これらの実験において、GABA±ステロイドを40ミリ秒間適用する。ほとんどすべての細胞において、第1のGABA適用が第2のGABA適用よりも小さな応答を与えたことが見出された。第2のGABA適用と第3のGABA適用との間の応答における違いはなかった。したがって、第1のGABA適用を常に2回反復し、第2の応答を分析において使用した。
生物学的評価。ヒトα1、β、γGABAA受容体サブタイプおよびα4、β、δGABAA受容体サブタイプにより恒久的にトランスフェクションされ、これらのGABAA受容体を発現するHEK-293細胞。
組み換えヒトα4、β3、δGABAA受容体は、GABAへの予想される正常な濃度応答曲線を示した(データ不掲載)。さらに、1μMの3β-ヒドロキシ-5α-プレグナン-20-オンのGABA媒介性電流応答は、α4、β3、δGABAA受容体サブタイプで、GABA単独に対して有意な効果がなかった(データ不掲載)。
GABAA受容体サブタイプα1、β2、γ2およびGABAA受容体サブタイプα4、β、δへの3β-ヒドロキシ-5α-プレグナン-20-オンの適用による実験。
トゥレット症候群、強迫性障害および/またはギャンブル障害の治療の生物学的効果を測定および確認できる複数の手法がある。1つの非限定実施例は、少なくともトゥレット症候群に関連して、Nordstrom & Burton 2002(Nordstrom,E.J.& Burton,F.H.A transgenic model of comorbid Tourette’s syndrome and obsessive-compulsive disorder circuitry.Mol.Psychiatry 7,617-625,524(2002))中で記載される遺伝子導入マウスモデルである。簡潔には、以下のように、実験を実行する。
ヘテロ接合のD1CT-7突然変異(約3か月齢)のオスBalb/cマウスは、およそ20~30gの体重である。動物をJackson Labs(Bar Harbor,ME)で購入し、到着時に遺伝子型を決定する。動物は、食物および水を自由に摂取させて群でケージ中に収容する。典型的には部屋を22℃で、午前8時~午後8時の12時間:12時間の明/暗サイクルで維持する。動物を午後12時~4時の間の明サイクルの間に試験して、任意の可能性のある概日の効果を最小限にする。
処理は、無作為化プロトコールにおいて、3β-ヒドロキシ-5α-プレグナン-20-オン(例えばMCTオイル中の懸濁物としてであるがこれらに限定されない)またはプラセボ(ベヒクル、例えばMCTオイル)の毎日の皮下注射である。
チック様所見を、Nordstrom and Burton(2002)に従って処理へ盲検化した訓練済の観察者によってスコアリングする。チック様所見は、頭および/または体の急速な(<1秒)の攣縮として定義される。
ノンパラメトリック統計を使用するだろう。有意性閾値は0.05でセットされ得る。
行動学的研究に参加しない動物の別のセットに、、毎日3日間適切な濃度の3β-ヒドロキシ-5α-プレグナン-20-オンを皮下に与え、血液サンプルを、3β-ヒドロキシ-5α-プレグナン-20-オンの血漿中濃度の決定のために異なるタイムポイント(2、4および8時間等)で採取する。
3β-ヒドロキシ-5α-プレグナン-20-オンは、GABAAステロイド調節物質アンタゴニストとして活性があり、したがって、トゥレット症候群、強迫性障害およびギャンブル障害の有る患者の視床中に所在する主要な受容体サブタイプにおいて、GABAA受容体調節ステロイドが誘導する促進をブロックすることができるので、本発明は、このように意外にもトゥレット症候群、強迫性障害およびギャンブル障害の可能な治療を提供する。
Claims (3)
- トゥレット症候群の治療における使用のための、3β-ヒドロキシ-5α-プレグナン-20-オンを含む医薬組成物。
- セロトニン再取込み阻害剤(SSRI)(シタロプラム、エシタロプラム(ecitalopram)、フルオキセチン、セルトラリンおよびフルボキサミンを包含する);5α-レデュカーゼ(reducase)ブロッカー(フィナステライドまたはデュタステライド包含する);定型および非定型神経弛緩薬(リスペルドン(risperdone)、ジプラシドン、ハロペリドール、ピモジドおよびフルフェナジンを包含する);降圧剤(クロニジン、グアンファシン、三環系抗鬱薬、クロミプラミンおよびオピオイドアンタゴニストを包含する)から選択される、少なくとも1つの活性化合物と組み合わせた使用のための、請求項1に記載の医薬組成物。
- 薬学的に許容される担体、賦形剤および/または希釈物質を含む、請求項1または2に記載の医薬組成物。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2022130080A JP2022159475A (ja) | 2017-02-10 | 2022-08-17 | 医学的治療における使用のための3-β-ヒドロキシ-5-α-プレグナン-20-オン |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE1750125 | 2017-02-10 | ||
SE1750125-5 | 2017-02-10 | ||
SE1751222 | 2017-10-03 | ||
SE1751222-9 | 2017-10-03 | ||
PCT/SE2018/050119 WO2018147792A1 (en) | 2017-02-10 | 2018-02-09 | 3-beta-hydroxy-5-alpha-pregnan-20-one for use in medical treatment |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2022130080A Division JP2022159475A (ja) | 2017-02-10 | 2022-08-17 | 医学的治療における使用のための3-β-ヒドロキシ-5-α-プレグナン-20-オン |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2020506182A JP2020506182A (ja) | 2020-02-27 |
JP2020506182A5 JP2020506182A5 (ja) | 2021-03-04 |
JP7179739B2 true JP7179739B2 (ja) | 2022-11-29 |
Family
ID=63107695
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019540059A Active JP7179739B2 (ja) | 2017-02-10 | 2018-02-09 | 医学的治療における使用のための3-β-ヒドロキシ-5-α-プレグナン-20-オン |
JP2022130080A Pending JP2022159475A (ja) | 2017-02-10 | 2022-08-17 | 医学的治療における使用のための3-β-ヒドロキシ-5-α-プレグナン-20-オン |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2022130080A Pending JP2022159475A (ja) | 2017-02-10 | 2022-08-17 | 医学的治療における使用のための3-β-ヒドロキシ-5-α-プレグナン-20-オン |
Country Status (11)
Country | Link |
---|---|
US (1) | US11026954B2 (ja) |
EP (1) | EP3579843A4 (ja) |
JP (2) | JP7179739B2 (ja) |
KR (1) | KR102478510B1 (ja) |
CN (1) | CN110430883A (ja) |
AU (1) | AU2018218823B2 (ja) |
BR (1) | BR112019015362A2 (ja) |
CA (1) | CA3049954A1 (ja) |
IL (1) | IL268265B (ja) |
MX (1) | MX2019008763A (ja) |
WO (1) | WO2018147792A1 (ja) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001008670A2 (en) | 1999-07-29 | 2001-02-08 | Interneuron Pharmaceuticals, Inc. | Methods and compositions for alleviating stuttering |
JP2002506034A (ja) | 1998-03-11 | 2002-02-26 | ベクストルム,トルビエーン | Cns疾患の治療におけるエピアロプレグナノロン |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5232917A (en) | 1987-08-25 | 1993-08-03 | University Of Southern California | Methods, compositions, and compounds for allosteric modulation of the GABA receptor by members of the androstane and pregnane series |
US5939545A (en) | 1994-02-14 | 1999-08-17 | Cocensys, Inc. | Method, compositions, and compounds for allosteric modulation of the gaba receptor by members of the androstane and pregnane series |
EP1047436B1 (en) * | 1998-01-13 | 2009-10-21 | Synchroneuron, LLC | N-acetylhomotaurinates for use in treating hyperkinesias |
US6855721B1 (en) * | 2000-07-28 | 2005-02-15 | Indevus Pharmaceuticals, Inc. | Methods and compositions for alleviating stuttering |
SE0104423D0 (sv) | 2001-12-27 | 2001-12-27 | Umecrine Ab | Pregnane steroids and their use in the treatment of CNS disorders |
US20040048876A1 (en) | 2002-02-20 | 2004-03-11 | Pfizer Inc. | Ziprasidone composition and synthetic controls |
CA2833976C (en) | 2006-11-21 | 2016-03-15 | Umecrine Ab | The use of pregnane and androstane steroids for the manufacture of a pharmaceutical composition for the treatment of cns disorders |
CN102753181B (zh) | 2010-01-14 | 2014-09-17 | 优麦克里尼穆德公司 | 具有改进的储存特性和溶解度特性的包含3-β-羟基-5-α-孕烷-20-酮的药物组合物 |
EP2875810A1 (en) * | 2013-11-20 | 2015-05-27 | Biocodex | Pharmacological treatment of obsessive-compulsive disorder using Stiripentol or a similar compound |
US9821023B2 (en) | 2014-06-10 | 2017-11-21 | The Arizona Board Of Regents On Behalf Of The University Of Arizona | Methods for the treatment of central nervous system (CNS) disorders and mood disorders |
JOP20200195A1 (ar) * | 2014-09-08 | 2017-06-16 | Sage Therapeutics Inc | سترويدات وتركيبات نشطة عصبياً، واستخداماتها |
WO2016114655A1 (en) | 2015-01-12 | 2016-07-21 | Ry Pharma B.V. | Treating neuromuscular or neurologic disease through reducing gabaergic and/or glycinergic inhibitory neurotransmitter overstimulation |
US20180311258A1 (en) * | 2015-04-10 | 2018-11-01 | Sage Therapeutics, Inc. | Compositions and methods for treating cns disorders |
RU2018101864A (ru) | 2015-06-22 | 2019-07-22 | Эмбера Ньюротерапьютикс, Инк. | Композиции и способы для лечения нарушений, связанных с употреблением веществ, зависимости и психических расстройств |
-
2018
- 2018-02-09 CN CN201880008675.7A patent/CN110430883A/zh active Pending
- 2018-02-09 WO PCT/SE2018/050119 patent/WO2018147792A1/en unknown
- 2018-02-09 MX MX2019008763A patent/MX2019008763A/es unknown
- 2018-02-09 BR BR112019015362-4A patent/BR112019015362A2/pt active Search and Examination
- 2018-02-09 KR KR1020197021969A patent/KR102478510B1/ko active IP Right Grant
- 2018-02-09 EP EP18751916.0A patent/EP3579843A4/en active Pending
- 2018-02-09 JP JP2019540059A patent/JP7179739B2/ja active Active
- 2018-02-09 CA CA3049954A patent/CA3049954A1/en active Pending
- 2018-02-09 AU AU2018218823A patent/AU2018218823B2/en active Active
- 2018-09-02 US US16/484,940 patent/US11026954B2/en active Active
-
2019
- 2019-07-25 IL IL268265A patent/IL268265B/en unknown
-
2022
- 2022-08-17 JP JP2022130080A patent/JP2022159475A/ja active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002506034A (ja) | 1998-03-11 | 2002-02-26 | ベクストルム,トルビエーン | Cns疾患の治療におけるエピアロプレグナノロン |
WO2001008670A2 (en) | 1999-07-29 | 2001-02-08 | Interneuron Pharmaceuticals, Inc. | Methods and compositions for alleviating stuttering |
Non-Patent Citations (2)
Title |
---|
Brain Research,2003年,Vol.982,p.45-53 |
Progress in Neuro-Psychopharmacology & Biological Psychiatry,2009年,Vol.33,p.1161-1166 |
Also Published As
Publication number | Publication date |
---|---|
CA3049954A1 (en) | 2018-08-16 |
JP2022159475A (ja) | 2022-10-17 |
US20190358245A1 (en) | 2019-11-28 |
AU2018218823B2 (en) | 2022-12-22 |
BR112019015362A2 (pt) | 2020-10-20 |
MX2019008763A (es) | 2019-10-21 |
IL268265B (en) | 2022-04-01 |
IL268265A (en) | 2019-09-26 |
KR102478510B1 (ko) | 2022-12-16 |
EP3579843A1 (en) | 2019-12-18 |
WO2018147792A1 (en) | 2018-08-16 |
EP3579843A4 (en) | 2020-12-23 |
KR20190117500A (ko) | 2019-10-16 |
JP2020506182A (ja) | 2020-02-27 |
AU2018218823A1 (en) | 2019-07-25 |
US11026954B2 (en) | 2021-06-08 |
CN110430883A (zh) | 2019-11-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Tuem et al. | Neuroactive steroids: receptor interactions and responses | |
Reddy | Neurosteroids: endogenous role in the human brain and therapeutic potentials | |
Bali et al. | Multifunctional aspects of allopregnanolone in stress and related disorders | |
JP5289281B2 (ja) | Cns疾患の治療において使用するためのプレグナンステロイド | |
Follesa et al. | Role of allopregnanolone in regulation of GABAA receptor plasticity during long-term exposure to and withdrawal from progesterone | |
WO2009142594A1 (en) | The use of 3beta-ethenyl, methyl, 3alpha-hydroxy-steroids for the treatment of cns disorders | |
Cutler et al. | Understanding the mechanism of action and clinical effects of neuroactive steroids and GABAergic compounds in major depressive disorder | |
King et al. | Neurosteroids and the nervous system | |
US8372824B2 (en) | GABA-steroid antagonists and their use for the treatment of CNS disorders | |
JP7179739B2 (ja) | 医学的治療における使用のための3-β-ヒドロキシ-5-α-プレグナン-20-オン | |
US11026953B2 (en) | 3-beta-hydroxy-5-alpha-pregnan-20-one for use in treatment of essential tremor | |
JP2021519799A (ja) | 物質離脱障害を治療するためのgaba−aアンタゴニスト | |
WO2023083980A1 (en) | Steroid as a modulator of gabaa receptor | |
RU2413516C2 (ru) | Гамк-стероидные антагонисты и их применение в лечении нарушений цнс | |
Broekhoven | Effects of progesterone and allopregnanolone on stress, attention, cognition and mood. | |
Lokhandwala et al. | Gonadal Hormones and Schizophrenia: A Clinical Review |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210121 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210121 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20211015 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20211125 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20220224 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20220418 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220817 |
|
C60 | Trial request (containing other claim documents, opposition documents) |
Free format text: JAPANESE INTERMEDIATE CODE: C60 Effective date: 20220817 |
|
C11 | Written invitation by the commissioner to file amendments |
Free format text: JAPANESE INTERMEDIATE CODE: C11 Effective date: 20220826 |
|
C876 | Explanation why request for accelerated appeal examination is justified |
Free format text: JAPANESE INTERMEDIATE CODE: C876 Effective date: 20220926 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20220926 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20221014 |
|
C21 | Notice of transfer of a case for reconsideration by examiners before appeal proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C21 Effective date: 20221017 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20221027 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20221116 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7179739 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |