EP0668764A1 - Verfahren zur identifikation und verwendung von opioidanalgetika mit niedrigem bzw. ohne abhängigkeitspotential - Google Patents

Verfahren zur identifikation und verwendung von opioidanalgetika mit niedrigem bzw. ohne abhängigkeitspotential

Info

Publication number: EP0668764A1
Authority: EP; European Patent Office
Prior art keywords: opioid; analgesic; dihydroetorphine; addictive; dhe
Prior art date: 1992-09-21
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 Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Withdrawn

Application number

EP93921686A

Other languages

English (en)

French (fr)

Inventor

Bo-Yi Qin

Ke-Fei Shen

Xiong-Qi Gong

Stanley M. Crain

Huang Mao

Chang Yi Wang

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Individual

Original Assignee

Individual

Priority date (The priority date 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 date listed.)

1992-09-21

Filing date

1993-09-17

Publication date

1995-08-30

1992-11-17 Priority claimed from US07/977,322 external-priority patent/US5410313A/en

1993-09-17 Application filed by Individual filed Critical Individual

1995-08-30 Publication of EP0668764A1 publication Critical patent/EP0668764A1/de

Status Withdrawn legal-status Critical Current

Links

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KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
238000001356 surgical procedure Methods 0.000 description 1
230000004083 survival effect Effects 0.000 description 1
238000013268 sustained release Methods 0.000 description 1
239000012730 sustained-release form Substances 0.000 description 1
238000010189 synthetic method Methods 0.000 description 1
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
238000012546 transfer Methods 0.000 description 1
230000003827 upregulation Effects 0.000 description 1
238000005353 urine analysis Methods 0.000 description 1
230000004584 weight gain Effects 0.000 description 1
235000019786 weight gain Nutrition 0.000 description 1
230000004580 weight loss Effects 0.000 description 1
108020001588 κ-opioid receptors Proteins 0.000 description 1
108020001612 μ-opioid receptors Proteins 0.000 description 1

Classifications

- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
- G01N33/9486—Analgesics, e.g. opiates, aspirine
- 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
- 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
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
- G01N2500/10—Screening for compounds of potential therapeutic value involving cells

Definitions

the present invention relates to a specific group of opioid agonists for use as low/non-addictive analgesics and for treatment of opioid addiction. More particularly, the present invention is directed to etorphine, dihydroetorphine, ohmefentanyl and other opioid and analogues thereof that are effective as low/non-addictive analgesics and for the treatment of opioid addiction. In addition, this invention provides a bioassay method to screen and identify such compounds with the ability to selectively activate inhibitory but not excitatory opioid receptor-mediated functions.
the present invention also relates to the preparation of etorphine, dihydroetorphine and analogues thereof using thebaine as the starting material. More specifically, the present invention relates to the preparation of dihydroetorphine hydrochloride (7o.-[l-(R)-hydroxy-1- methylbutyl]-6,14-endo-ethano-tetrahydrooripavine hydrochloride) and pharmaceutical compositions thereof.
opioid compounds are identified by recording the action potential duration (APD) of a sensory neuron elicited by the compound in a cell culture screening assay and selecting those opioid compounds which shorten the APD but do not prolong the APD relative to a control APD when the compounds are assayed in the concentration range of about fM to about / xM. Opioid compounds with these characteristics are thereby identified as low- or non-addictive opioid analgesics of the invention.
API action potential duration
the cell culture screening assay comprises exposing a dorsal-root ganglion (DRG) neuron to the candidate compound, typically by bath perfusion, applying a brief intracellular depolarizing current to said DRG neuron, and recording opioid-induced alteration in the APD of the DRG neuron using standard electrophysiological techniques.
DRG dorsal-root ganglion
Another aspect of the invention provides low- or non-addictive analgesics, particularly as identified by the method of the present invention, which are capable of evoking the inhibitory but not the excitatory effects of opioid receptor-mediated functions, particularly on sensory neurons, in a dose-dependent manner in concentrations ranging from about fM to about ⁇ M.
these opioids include etorphine, dihydroetorphine or ohmefentanyl.
Pharmaceutical compositions containing the subject low- or non-addictive opioids, or pharmaceutically acceptable salts thereof, together with pharmaceutically acceptable carriers are also provided.
the subject pharmaceutical compositions can also contain a replacement opioid or naloxone.
opioid addiction is treated by administering about 40 to about 500 ⁇ g of dihydroetorphine per day to a patient for about one to about three days, administering a decreasing amount of dihydroetorphine for the following about four to about seven days so that no further dihydroetorphine is necessary by about 10 days after the first administration of dihydroetorphine.
Fig. 5 illustrates that chronic exposure of a DRG neuron to a bimodally acting opioid (DADLE) causes the DRG neuron to become supersensitive to the excitatory effects of dynorphin (1-13) (Dyn) , whereas perfusion of etorphine effectively shortened the APD of the same DRG neuron
Fig. 9 depicts the withdrawal symptom scores after naloxone precipitation for DHE and methadone substitution in morphine-dependent rats. Rats were treated as described in Fig. 8.
Column A Withdrawal scores from the first naloxone precipitation test.
Column B Withdrawal scores from the second naloxone precipitation test.
Statistical p values between the first and second naloxone precipitation test are ••**", p ⁇ 0.05 and ••*** » , p ⁇ 0.01.
the p value for the DHE group relative to the methadone group is p ⁇ 0.01.
the potent inhibitory effect exerted by the low- or non-addictive opioid analgesics of this invention can block or suppress the excitatory effects of bimodally- acting opioids, i.e. the replacement opioid as defined herein, to alleviate tolerance and addiction commonly observed by sole usage of bimodally-acting opioids (e.g. morphine or methadone) .
bimodally-acting opioids e.g. morphine or methadone
DRG neurons are supersensitive to the excitatory effects of opioids (Crain & Shen 1992a; Shen & Crain, 1992) .
pM-nM Dyn amino acid 1-13
fM levels and lower are effective at prolonging the APD after chronic opioid treatment (Fig. 5, traces 1-4) .
acute application of etorphine to chronic DADLE-treated neurons effectively shortened the APD of the same DRG neurons that showed supersensitive excitatory responses to low concentrations of bimodally- acting opioids (Fig. 5, traces 6-9).

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Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Engineering & Computer Science (AREA)
Molecular Biology (AREA)
Chemical & Material Sciences (AREA)
General Health & Medical Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Medicinal Chemistry (AREA)
Immunology (AREA)
Biomedical Technology (AREA)
Urology & Nephrology (AREA)
Hematology (AREA)
Emergency Medicine (AREA)
Epidemiology (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
Animal Behavior & Ethology (AREA)
Biotechnology (AREA)
Physics & Mathematics (AREA)
Analytical Chemistry (AREA)
Biochemistry (AREA)
Bioinformatics & Cheminformatics (AREA)
General Physics & Mathematics (AREA)
Pathology (AREA)
Microbiology (AREA)
Food Science & Technology (AREA)
Cell Biology (AREA)
Pain & Pain Management (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

EP93921686A 1992-09-21 1993-09-17 Verfahren zur identifikation und verwendung von opioidanalgetika mit niedrigem bzw. ohne abhängigkeitspotential Withdrawn EP0668764A1 (de)

Applications Claiming Priority (7)

Application Number	Priority Date	Filing Date	Title
US94769092A	1992-09-21	1992-09-21
US947690		1992-09-21
US977322		1992-11-17
US07/977,322 US5410313A (en)	1992-11-17	1992-11-17	Functional radar warning receiver back-up generator
US8850393A	1993-07-07	1993-07-07
US88503		1993-07-07
PCT/US1993/008869 WO1994006426A1 (en)	1992-09-21	1993-09-17	Methods for identifying and using low/non-addictive opioid analgesics

Publications (1)

Publication Number	Publication Date
EP0668764A1 true EP0668764A1 (de)	1995-08-30

Family

ID=27375994

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
EP93921686A Withdrawn EP0668764A1 (de)	1992-09-21	1993-09-17	Verfahren zur identifikation und verwendung von opioidanalgetika mit niedrigem bzw. ohne abhängigkeitspotential

Country Status (4)

Country	Link
EP (1)	EP0668764A1 (de)
JP (1)	JPH08504189A (de)
CA (1)	CA2145207A1 (de)
WO (1)	WO1994006426A1 (de)

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Also Published As

Publication number	Publication date
WO1994006426A1 (en)	1994-03-31
JPH08504189A (ja)	1996-05-07
CA2145207A1 (en)	1994-03-22

Publication	Publication Date	Title
EP0668764A1 (de)	1995-08-30	Verfahren zur identifikation und verwendung von opioidanalgetika mit niedrigem bzw. ohne abhängigkeitspotential
US5624932A (en)	1997-04-29	Method for identification of low/non-addictive opioid analgesics and the use of said analgesics for treatment of opioid addiction
EP1327447B1 (de)	2011-05-25	Noribogain zur Behandlung von Schmerzen und Drogenabhängigkeit
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EP1617832B1 (de)	2008-03-12	Zusammensetzungen zur beeinflussung des gewichtsverlusts
US7220737B1 (en)	2007-05-22	Noribogaine in the treatment of pain and drug addiction
JP3115119B2 (ja)	2000-12-04	トラマドールｎ−オキシド材料、そのエナンチオマー及び組成物、ならびにその利用
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HK1032542B (en)	2003-07-25	Combination for the treatment of alcohol dependence containing an opioid antagonist and a nmda receptor complex modulator
MXPA00009454A (es)	2001-07-31	Metodos y composiciones para tratar rinitis alergica y otros trastornos usando descarboetoxiloratadina

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