CA1258674A - Agonistes et antagonistes des opiaces - Google Patents
Agonistes et antagonistes des opiacesInfo
- Publication number
- CA1258674A CA1258674A CA000413566A CA413566A CA1258674A CA 1258674 A CA1258674 A CA 1258674A CA 000413566 A CA000413566 A CA 000413566A CA 413566 A CA413566 A CA 413566A CA 1258674 A CA1258674 A CA 1258674A
- Authority
- CA
- Canada
- Prior art keywords
- compound
- naloxazone
- binding
- naloxonazine
- hdm
- 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
Links
- 239000003401 opiate antagonist Substances 0.000 title description 4
- 239000003402 opiate agonist Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 230000027455 binding Effects 0.000 claims abstract description 35
- 125000002993 cycloalkylene group Chemical group 0.000 claims abstract description 5
- 229960001410 hydromorphone Drugs 0.000 claims abstract description 5
- -1 Dihydromorphinone compound Chemical class 0.000 claims abstract description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 3
- AJPSBXJNFJCCBI-YOHUGVJRSA-N naloxonazine Chemical compound C([C@@H](N(CC1)CC=C)[C@]2(O)CC\C3=N/N=C4/[C@H]5[C@]67CCN(CC=C)[C@@H]([C@@]7(CC4)O)CC4=CC=C(C(O5)=C46)O)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 AJPSBXJNFJCCBI-YOHUGVJRSA-N 0.000 claims description 32
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 23
- GSYDZKZBXPTRGD-QWLHVPTFSA-N (4r,4as,7e,7ar,12bs)-7-[(e)-[(4r,4as,7ar,12bs)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ylidene]hydrazinylidene]-3-(cyclopropylmethyl)-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]\5[C@](C3=4)([C@]2(CCC/5=N\N=C/2[C@@H]3OC=4C(O)=CC=C5C[C@@H]6[C@]([C@@]3(CCN6CC3CC3)C5=4)(O)CC\2)O)CC1)O)CC1CC1 GSYDZKZBXPTRGD-QWLHVPTFSA-N 0.000 claims description 14
- WKXKOQQVFYOJBC-MZODVJCESA-N (4r,4as,7e,7ar,12bs)-7-[(e)-[(4r,4as,7ar,12bs)-4a,9-dihydroxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ylidene]hydrazinylidene]-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,9-diol Chemical compound C([C@@H](N(CC1)C)[C@]2(O)CC/C3=N\N=C4/CC[C@@]5(O)[C@H]6CC=7C8=C(C(=CC=7)O)O[C@@H]4[C@]85CCN6C)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 WKXKOQQVFYOJBC-MZODVJCESA-N 0.000 claims description 13
- UQCNKQCJZOAFTQ-ISWURRPUSA-N Oxymorphone Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O UQCNKQCJZOAFTQ-ISWURRPUSA-N 0.000 claims description 12
- 229960005118 oxymorphone Drugs 0.000 claims description 10
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 4
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 claims description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 2
- 125000002070 alkenylidene group Chemical group 0.000 claims 1
- AABLHGPVOULICI-BRJGLHKUSA-N hydromorphinol Chemical group O([C@H]1[C@H](CC[C@]23O)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O AABLHGPVOULICI-BRJGLHKUSA-N 0.000 claims 1
- 102000003840 Opioid Receptors Human genes 0.000 abstract description 11
- 108090000137 Opioid Receptors Proteins 0.000 abstract description 11
- 230000000903 blocking effect Effects 0.000 abstract description 4
- 125000002947 alkylene group Chemical group 0.000 abstract 2
- 125000000547 substituted alkyl group Chemical group 0.000 abstract 2
- 125000003342 alkenyl group Chemical group 0.000 abstract 1
- 125000003118 aryl group Chemical group 0.000 abstract 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 abstract 1
- 125000006588 heterocycloalkylene group Chemical group 0.000 abstract 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract 1
- XQQRNWNMEFUSMN-UTWDOOMRSA-N (4r,4as,7e,7ar,12bs)-7-hydrazinylidene-3-prop-2-enyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,9-diol Chemical compound C([C@@H](N(CC1)CC=C)[C@]2(O)CC\C3=N/N)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 XQQRNWNMEFUSMN-UTWDOOMRSA-N 0.000 description 40
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 34
- 229960004127 naloxone Drugs 0.000 description 28
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 27
- 229940079593 drug Drugs 0.000 description 20
- 239000003814 drug Substances 0.000 description 20
- 230000009471 action Effects 0.000 description 17
- 229960005181 morphine Drugs 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 230000000694 effects Effects 0.000 description 14
- 230000002427 irreversible effect Effects 0.000 description 14
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 13
- 229960003086 naltrexone Drugs 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 12
- 150000007857 hydrazones Chemical class 0.000 description 12
- 230000005764 inhibitory process Effects 0.000 description 11
- 229940127240 opiate Drugs 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- 102000005962 receptors Human genes 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 241000700159 Rattus Species 0.000 description 9
- RCNYWXCENWWKDS-VTRZFGTDSA-N (4r,4as,7e,7ar,12bs)-3-(cyclopropylmethyl)-7-hydrazinylidene-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,9-diol Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC\C3=N/N)CN2CC1CC1 RCNYWXCENWWKDS-VTRZFGTDSA-N 0.000 description 8
- IJVCSMSMFSCRME-KBQPJGBKSA-N Dihydromorphine Chemical compound O([C@H]1[C@H](CC[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O IJVCSMSMFSCRME-KBQPJGBKSA-N 0.000 description 8
- 230000036592 analgesia Effects 0.000 description 8
- 210000004556 brain Anatomy 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 239000012528 membrane Substances 0.000 description 7
- VOFTYIFRRWVMOO-FDUMSJNMSA-N oxymorphazone Chemical compound O([C@H]1C(/CC[C@]23O)=N/N)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O VOFTYIFRRWVMOO-FDUMSJNMSA-N 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 108010051696 Growth Hormone Proteins 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- 102100038803 Somatotropin Human genes 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000000122 growth hormone Substances 0.000 description 6
- 239000005556 hormone Substances 0.000 description 6
- 229940088597 hormone Drugs 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 102100024819 Prolactin Human genes 0.000 description 5
- 108010057464 Prolactin Proteins 0.000 description 5
- 238000006073 displacement reaction Methods 0.000 description 5
- 229940097325 prolactin Drugs 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 229930013930 alkaloid Natural products 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical class O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- ANZXICRKKYOVMY-UHFFFAOYSA-N 2-[[2-[[2-[2-[[2-amino-3-(4-hydroxyphenyl)propanoyl]amino]propanoylamino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylsulfanylbutanamide Chemical compound C=1C=C(O)C=CC=1CC(N)C(=O)NC(C)C(=O)NCC(=O)NC(C(=O)NC(CCSC)C(N)=O)CC1=CC=CC=C1 ANZXICRKKYOVMY-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 150000003797 alkaloid derivatives Chemical class 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 238000000159 protein binding assay Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- VOFTYIFRRWVMOO-ISWURRPUSA-N (4r,4as,7ar,12bs)-7-hydrazinylidene-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,9-diol Chemical class O([C@H]1C(CC[C@]23O)=NN)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O VOFTYIFRRWVMOO-ISWURRPUSA-N 0.000 description 2
- NHJVRSWLHSJWIN-UHFFFAOYSA-N 2,4,6-trinitrobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O NHJVRSWLHSJWIN-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- URLZCHNOLZSCCA-VABKMULXSA-N Leu-enkephalin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 URLZCHNOLZSCCA-VABKMULXSA-N 0.000 description 2
- OZYUPQUCAUTOBP-QXAKKESOSA-N Levallorphan Chemical compound C([C@H]12)CCC[C@@]11CCN(CC=C)[C@@H]2CC2=CC=C(O)C=C21 OZYUPQUCAUTOBP-QXAKKESOSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000036528 appetite Effects 0.000 description 2
- 235000019789 appetite Nutrition 0.000 description 2
- 239000002830 appetite depressant Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000002051 biphasic effect Effects 0.000 description 2
- 230000000994 depressogenic effect Effects 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 229960000263 levallorphan Drugs 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229940067157 phenylhydrazine Drugs 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 230000009834 selective interaction Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RJEUERNNQHNSKG-CCKFTAQKSA-N (2s)-2-amino-n-[(2r)-1-[[2-[[(2s)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]amino]-1-oxopropan-2-yl]-3-(4-hydroxyphenyl)propanamide Chemical compound C([C@H](N)C(=O)N[C@H](C)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)C1=CC=C(O)C=C1 RJEUERNNQHNSKG-CCKFTAQKSA-N 0.000 description 1
- JSFGIWIHCRVLSN-HTNFSKGQSA-N (4R,4aR,7aR,12bS)-3-methyl-2,4,4a,13-tetrahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7,7,7a,9-tetrol Chemical compound OC1([C@]2([C@]34C=5C(=C(C=CC=5C[C@H]([C@@H]3C=C1)N(C)CC4)O)O2)O)O JSFGIWIHCRVLSN-HTNFSKGQSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- XUDUTRMKKYUAKI-UHFFFAOYSA-N 3-[1-(1-phenylethyl)piperidin-4-yl]-1h-benzimidazol-2-one Chemical compound C1CC(N2C(NC3=CC=CC=C32)=O)CCN1C(C)C1=CC=CC=C1 XUDUTRMKKYUAKI-UHFFFAOYSA-N 0.000 description 1
- KMVPXBDOWDXXEN-UHFFFAOYSA-N 4-nitrophenylhydrazine Chemical compound NNC1=CC=C([N+]([O-])=O)C=C1 KMVPXBDOWDXXEN-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 101710125089 Bindin Proteins 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 241000182341 Cubitermes group Species 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 238000000729 Fisher's exact test Methods 0.000 description 1
- 241000243251 Hydra Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 229910017974 NH40H Inorganic materials 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000000451 chemical ionisation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000020595 eating behavior Effects 0.000 description 1
- JPGQOUSTVILISH-UHFFFAOYSA-N enflurane Chemical compound FC(F)OC(F)(F)C(F)Cl JPGQOUSTVILISH-UHFFFAOYSA-N 0.000 description 1
- 229960000305 enflurane Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000004634 feeding behavior Effects 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 239000003509 long acting drug Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 238000004452 microanalysis Methods 0.000 description 1
- 229960004715 morphine sulfate Drugs 0.000 description 1
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 description 1
- 102000051367 mu Opioid Receptors Human genes 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229940124636 opioid drug Drugs 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 150000004031 phenylhydrazines Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 108020001612 μ-opioid receptors Proteins 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US31201881A | 1981-10-16 | 1981-10-16 | |
| US312,018 | 1989-02-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1258674A true CA1258674A (fr) | 1989-08-22 |
Family
ID=23209508
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000413566A Expired CA1258674A (fr) | 1981-10-16 | 1982-10-15 | Agonistes et antagonistes des opiaces |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPS5883680A (fr) |
| CA (1) | CA1258674A (fr) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IN163125B (fr) * | 1985-01-08 | 1988-08-13 | Alkaloida Vegyeszeti Gyar |
-
1982
- 1982-10-15 CA CA000413566A patent/CA1258674A/fr not_active Expired
- 1982-10-16 JP JP18203282A patent/JPS5883680A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5883680A (ja) | 1983-05-19 |
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