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

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• 1993
  • 1993-09-17 WO PCT/US1993/008869 patent/WO1994006426A1/en not_active Application Discontinuation
  • 1993-09-17 JP JP6508375A patent/JPH08504189A/ja active Pending
  • 1993-09-17 EP EP93921686A patent/EP0668764A1/de not_active Withdrawn
  • 1993-09-17 CA CA002145207A patent/CA2145207A1/en not_active Abandoned

Non-Patent Citations (1)

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