WO2024044179A1 - Ligands de récepteurs opioïdes à ciblage multiple utilisés en tant que nouveaux analgésiques avec risque d'abus minimal - Google Patents

Ligands de récepteurs opioïdes à ciblage multiple utilisés en tant que nouveaux analgésiques avec risque d'abus minimal Download PDF

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WO2024044179A1
WO2024044179A1 PCT/US2023/030810 US2023030810W WO2024044179A1 WO 2024044179 A1 WO2024044179 A1 WO 2024044179A1 US 2023030810 W US2023030810 W US 2023030810W WO 2024044179 A1 WO2024044179 A1 WO 2024044179A1
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compound
compounds
mice
nmf
kor
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PCT/US2023/030810
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Yan Zhang
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Virginia Commonwealth University
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    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention generally relates to multi-opioid receptor ligands for pain relief without causing addiction.
  • the invention provides opioid receptor ligands with conjoint targeting of at least mu opioid receptor (MOR) and kappa opioid receptor (KOR), to effectively treat pain without causing addiction and abuse.
  • MOR mu opioid receptor
  • KOR kappa opioid receptor
  • MOR mu opioid receptor
  • KOR kappa opioid receptor
  • DOR delta opioid receptor
  • NOP nociception/orphanin FQ peptide receptor
  • activation of any of them may mediate analgesic effects.
  • agonists of the KOR, DOR, and NOP also carry side effects, such as dysphoria, seizures, and altered renal function, respectively, none of them cause euphoria or severe dependence like MOR agonists.
  • selective agonists solely targeting the KOR, DOR, or NOP have not achieved satisfactory clinical results.
  • Nalfurafine (NFU, Figure 1) is a potent MOR/KOR dual agonist which is used in Japan as an antipruritic for hemodialysis patients, has also showed potent analgesia in a variety of pain models.
  • Other examples of clinically efficacious dual MOR/KOR agonists such as pentazocine, nalbuphine, and dihydroetorphine ( Figure 1).
  • these agonists still retain the limitations of MOR agonists including abuse liability and respiratory depression.
  • analgesics devoid of abuse liability is critical to battle the opioid crisis in the US and elsewhere.
  • the examples of the present disclosure describe a complementary structure- activity relationship (SAR) study that systematically explored multi-opioid receptor pharmacology of Nalfurafine (NFU) analogs.
  • SAR complementary structure- activity relationship
  • NFU Nalfurafine
  • R 1 is H or OH
  • R 2 is H or CH 3 ;
  • R 3 is a heterocyclic system or where
  • X O, NH or S
  • X’, W, Y and Z are independently CH or N;
  • Q includes a saturated or unsaturated, branched or unbranched, substituted or unsubstituted alkyl group having from 2 to 10 carbon atoms; with the caveat that the compound cannot be
  • R 1 is OH
  • R 2 is CH3 and * is either alpha or beta; and pharmaceutically acceptable salts thereof.
  • the one or more carbon atoms of Q are independently substituted with one or more heteroatoms or heteroatomic groups selected from the group consisting of N, O, OH, SO, SO 2 , COOH, N, NH, NH 2 , NH 3 + , PO, PO 2 , PO3, and halogen.
  • Q includes a double bond
  • R 3 is a furan ring attached via C at position 3, and * is a or p.
  • Q includes a single bond or or double bond, R 3 is a furan ring attached via C at popsition 2 or C at position 3; and * is a or p.
  • the compound is and * is p.
  • R 1 is H or OH
  • R 2 is H or CH 3 ;
  • R 3 is a heterocyclic system or where
  • X O, NH or S
  • X’, W, Y and Z are independently CH or N;
  • Q includes a saturated or unsaturated, branched or unbranched, substituted or unsubstituted alkyl group having from 2 to 10 carbon atoms; or a pharmaceutically acceptable salt thereof; wherein administration of the at lease one compound does not cause addiction thereto.
  • the one or more carbon atoms of Q are independently substituted with one or more heteroatoms or heteroatomic groups selected from the group consisting of N, O, OH, SO, SO 2 , COOH, N, NH, NH 2 , NH 3 + , PO, PO 2 , PO 3 , or halogen.
  • Q includes a double bond, R 3 is a furan ring attached via C at position 3, and * is a or p.
  • Q includes a single bond or or double bond, R 3 is a furan ring attached via C at popsition 2 or C at position 3; and * is a or p.
  • the at least one compound is and * is a.
  • the at least one compound is and * is p.
  • Figure 1 Prior art compounds that target one or more opioid receptors.
  • FIG. 4 Blocking the antinociceptive effects of NMF by selective KOR antagonist and DOR antagonist in warm water tail immersion assay, respectively.
  • nor-BNI and P-FNA were given s.c. at a dose of 10 mg/kg 24 h prior to 0.1 mg/kg NMF administration.
  • NTI was injected s.c. at a dose of 15 mg/kg 30 minutes prior to 0.1 mg/kg NMF injection.
  • Figure 5 Time course study of NMF and morphine. (All administration routes were s.c. compared to vehicle: *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001, *p ⁇ 0.0001; Compared with the morphine group: AA p ⁇ 0.01, AAA p ⁇ 0.001, AAAA p ⁇ 0.0001. Error bars represent SD.
  • FIG. 7A-C Drug tolerance and cross tolerance.
  • A Experimental design. Mice were administered a vehicle, 10 mg/kg morphine, 0.1 mg/kg NMF or 0.5 mg/kg NMF twice daily for consecutive four days, (s.c.)
  • B Antinociceptive effects of compounds were evaluated daily. Compared with DI (day 1), *p ⁇ 0.05, ***p ⁇ 0.001.
  • C On day 5, vehicle, 10 mg/kg morphine or 0.1 mg/kg NMF was given to the morphine-treated group, after which the warmwater tail immersion assay was again performed. *p ⁇ 0.05, **p ⁇ 0.01. Error bars represent SD.
  • Figure 8A-D Weight change in mice received chronic administration of vehicle (8 A), NMF 0.1 mg/kg (8B), NMF 0.5 mg/kg (8C) or morphine (8D) compared to Day 1, *p ⁇ 0.05, ****p ⁇ 0.0001. Error bars represent SD.
  • Figure 9 Withdrawal and diarrhea symptoms precipitated by naloxone (NEX) in chronic analgesic-administration mice.
  • NEX naloxone
  • morphine pellet group *p ⁇ 0.05, **p ⁇ 0.01, ****p ⁇ 0.0001.
  • Percentage of diarrhea was calculated as the number of mice who had diarrhea divided by the total mouse number in each group. The severity of diarrhea was not quantified. Error bars represent SEM.
  • FIG. 10A-C The respiratory effects of NMF and morphine in mice.
  • FIG 11A-C Spontaneous locomotor activity change after drug administration.
  • Activity data was recorded for 30 min with the injection time as time zero.
  • ns no significant difference at p ⁇ 0.05. Error bars represent SD.
  • A Timeline for testing procedure. Abscissa: Compound and dose studied in mg/kg.
  • B and F Ordinate: Total distance travelled during the 30 min session in centimeters.
  • C and G Ordinate: Total ambulatory counts in the 30 min session.
  • D and H Ordinate: Total vertical counts during the 30 min session.
  • E and I Ordinate: Average speed during the 30 min session in centimeters/second. All bars represent the mean ⁇ SEM. *Denotes significant difference relative to the vehicle condition (white bar), defined as p ⁇ 0.05.
  • Figure 21A-C Self-administration of fentanyl and test compounds in male and female rats (A: 2M,6F; B: 2M,6F; C: 3M,6F). Ordinate: Number of infusions earned under a FR5 schedule of reinforcement. Abscissa: Intravenous unit dose of compound infusion in pg/kg/inf with compound being fentanyl (A-C), nalfurafine (A), compound 21 (B) or compound 23 (NCF; C).
  • Saline and “Fent” represent the mean ⁇ SEM of all saline and 3.2 pg/kg/inf fentanyl days obtained as baselines between the testing days needed to acquire the respective dose-effect curves shown in A-C. All points represent the mean ⁇ SEM. *Denotes significant difference relative to saline, defined as p ⁇ 0.05.
  • A Graphical experimental procedure for tolerance assay.
  • B - D Development of tolerance (or lack thereof) in morphine and vehicle groups as well as nalfurafine (NLF; B), compound 21 (C), compound 23 (NCF; D).
  • Ordinate percent maximum possible effect (MPE). Abscissa: Test day. All points represent the mean ⁇ SEM. *Denotes significant difference relative to test day 1, defined as p ⁇ 0.05.
  • E Graphical experimental procedure for cross-tolerance assay.
  • A Graphical experimental procedure (NLX: naloxone).
  • B Ordinate: Mean count of observed withdrawal signs. Abscissa: Compounds given at specified doses in mg/kg. All points represent the mean ⁇ SEM. *Denotes significant difference relative to the morphine (10 mg/kg) group, defined as p ⁇ 0.05.
  • analgesic compounds that bind to at least two (more than one) of the opioid receptors mu opioid receptor (MOR), kappa opioid receptor (KOR), delta opioid receptor (DOR), and nociception/orphanin FQ peptide receptor (NOP).
  • MOR mu opioid receptor
  • KOR kappa opioid receptor
  • DOR delta opioid receptor
  • NOP nociception/orphanin FQ peptide receptor
  • ADMET study is the assessment of pharmacokinetics of a drug which stands for Absorption, Distribution, Metabolism, Excretion and Toxicity.
  • the hERG channel inhibition assay is a highly sensitive measurement which will identify compounds exhibiting cardiotoxicity related to hERG inhibition in vivo. However, not all compounds which inhibit hERG activity in vitro cause cardiotoxicity in vivo.
  • a functional derivative (or functional analog) of a compound is a compound that has been or can be synthesized from another compound and differs therefrom by the replacement of 1-3 atoms or 1-3 functional groups of atoms (e.g., H replaced by methyl, ethyl, etc.; replacement of O by S or N, or vice versa; replacement of carboxyl, amide, etc. with an atom or a different functional group, and the like).
  • Functional derivatives exhibit the same or highly similar chemical and/or biochemical properties and/or activities (e.g., physical, chemical, biochemical, and/or pharmacological properties/activities) as the compound from which they are derived, when the original compound from which they are derived and the functional derivative are tested under the same conditions.
  • the value may be higher or lower than the value of the property or activity of the original compound by about 50%-150% (e.g., about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145 or 150%).
  • Methods of making and tests for identifying functional derivatives include those described in the Examples section of this disclosure.
  • * represents an alpha or beta configuration at carbon number 6 of the ring
  • R 1 is H or OH
  • R 2 is H or methyl (CH3)
  • R 3 is a heterocyclic system
  • X O, NH or S
  • X’, W, Y and Z are independently CH or N;
  • Q includes a saturated or unsaturated, branched or unbranched (i.e., straight chain, linear), substituted or unsubstituted alkyl group having from 2 to 10 carbon atoms; and pharmaceutically acceptable salts and functional derivatives thereof.
  • the compounds have a general formula as shown for Formula I and
  • Q includes a single, double (cis or trans) or triple bond, and C) i.e., a furan ring, and is attached to the rest of the molecule at the carbon atom at position 2 or 3, both of which are indicated on the ring; with the caveat that the compound per se cannot be where R 1 is OH, R 2 is CH3 and * is either alpha or beta.
  • one or more carbon atoms of Q are independently substituted with one or more heteroatoms or heteroatomic groups, including but not limited to: S, N, O, halogen (e.g., Cl, F, I), OH, SO, SO 2 , COOH, N, NH, NH 2 , NH 3 + , PO, PO 2 , PO3, etc.
  • halogen e.g., Cl, F, I
  • R 1 is H or OH
  • R 2 is H or CH3
  • Q includes a single bond or a double bond
  • a saturated carbon group or chain (alkane; aliphatic hydrocarbon) has only single covalent bonds between adjacent C atoms throughout the group, whether the group is a straight or branched chain.
  • exemplary univalent radicals of saturated carbon groups or chains included in the variable groups of Q include but are not limited to: methyl (CH3), ethyl (C2H5), propyl (C3H7), isopropyl, butyl (C4H9, including n-butyl, s-butyl, t-butyl), pentyl (C5H11), hexyl (CeHn), heptyl (C7H15), octyl (CsHn), nonyl (C9H19) and decyl (C10H21).
  • lower alkyls comprising from 1-6 C atoms are also encompassed as are branched saturated alkane radicals including but are not limited to: isobutyl, isopentyl, neopentyl, various isohexyls, and the like.
  • An unsaturated or partially unsaturated carbon group or chain has one or more (at least one) covalent double bond between two adjacent carbon atoms (alkene); and/or at least one covalent triple bond(s) between two adjacent C atoms (alkyne).
  • alkene radicals having one double bond include but are not limited to: methenyl, ethenyl, propenyl, butenyl (e.g., 2-butenyl), pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc., and branched chains thereof.
  • Exemplary alkyne radicals having one triple bond include but are not limited to: ethyne, propyne, butyne (e.g., 2-butynyl), pentyne, hexyne, heptyne, octyne, nonyne, etc.
  • Di- and tri-alkene radicals comprising, respectively, 2 or 3 double bonds or more are also encompassed as are di- and tri-alkyne radicals comprising, respectively, 2 or 3 or more triple bonds.
  • substituted refers to the addition of one or more substituents by replacement of a carbon atom or as an attachment to a carbon atom.
  • substituents are halogen, haloalkyl, alkyl, acyl, hydroxyalkyl, hydroxy, alkoxy, haloalkoxy, aminocarbonyl oxaalkyl, carboxy, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino arylsulfonyl, arylsulfonylamino, and benzyloxy.
  • Additional examples include: substituted alkyl, aryl, cycloalkyl, etc., wherein one or more H atoms are replaced with halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxy lower alkyl, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, lower alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylamino, aminocarbonyl (also known as carboxamido), alkylaminocarbonyl, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl (including cycloalkylaminoalkyl), dialkylaminoalkyl, dialkylaminoalkoxy, heterocyclylalkoxy, mercapto, al
  • Oxo is also included among the substituents referred to in "independently substituted". It will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g., on phenyl). In one embodiment, 1, 2, or 3 hydrogen atoms are replaced with a specified radical.
  • Exemplary compounds include but are not limited to: wherein * is p.
  • compositions generally comprise at least one of the disclosed compounds, i.e., one or more than one (a plurality) of the compounds (e.g., 2 or more such as 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) may be included in a single formulation. Accordingly, the present invention encompasses such formulations/compositions.
  • the compositions generally include one or more substantially purified compounds as described herein, and a pharmacologically suitable (physiologically compatible) carrier. In some aspects, such compositions are prepared as liquid solutions or suspensions, or as solid forms such as tablets, pills, powders and the like.
  • Solid forms suitable for solution in, or suspension in, liquids prior to administration are also contemplated (e.g., lyophilized forms of the compounds), as are emulsified preparations.
  • the formulations are liquid and are aqueous or oil-based suspensions or solutions.
  • the active ingredients are mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredients, e.g., pharmaceutically acceptable salts.
  • suitable excipients include, for example, water, saline, dextrose, glycerol, ethanol and the like, or combinations thereof.
  • the composition may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, preservatives, and the like. If it is desired to administer an oral form of the composition, various thickeners, flavorings, diluents, emulsifiers, dispersing aids or binders and the like are added.
  • composition of the present invention may contain any such additional ingredients so as to provide the composition in a form suitable for administration.
  • the final amount of compound in the formulations varies but is generally from about 1-99%.
  • Still other suitable formulations for use in the present invention are found, for example in Remington's Pharmaceutical Sciences, 22nd ed. (2012; eds. Allen, Adejarem Desselle and Felton).
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as Tween® 80, phosphates, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, methylcellulose, hydroxypropyl methylcellulose, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose a
  • “Pharmaceutically acceptable salts” of the compounds refers to the relatively nontoxic, inorganic and organic acid addition salts and base addition salts of compounds of the present disclosure. In some aspects, these salts are prepared in situ during the final isolation and purification of the compounds. In particular, acid addition salts can be prepared by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Exemplary acid addition salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, sulfamates, malonates, salicylates, propionates, methylene-bis-P-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and lauryls
  • Base addition salts can also be prepared by separately reacting the purified compound in its acid form with a suitable organic or inorganic base and isolating the salt thus formed.
  • Base addition salts include pharmaceutically acceptable metal and amine salts.
  • Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium, and aluminum salts.
  • Suitable inorganic base addition salts are prepared from metal bases which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide and the like.
  • Suitable amine base addition salts are prepared from amines which have sufficient basicity to form a stable salt, and preferably include those amines which are frequently used in medicinal chemistry because of their low toxicity and acceptability for medical use.
  • ammonia ethylenediamine, N- methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine,
  • the compounds may also be formulated for delayed, controlled, long-acting and/or sustained release.
  • formulations including those described in published US patent applications US20210113469A1 US11179369B2, US 10463624B2, US 10624905B2, US 11090269B 1 and US 11110093B2, the complete contents of which are hereby incorporated by reference in entirety.
  • the formulation comprises one or more microparticles comprising one or more of the compounds, for example, pellets, beads, tablets, spheroids, liposomes, gels, or combinations of two or more of these.
  • a pill or tablet is used for delivery, the tablet comprising a coating layer disposed on a core, the coating layer including at least one release rate controlling polymer and the core comprising the pharmacologically active compound(s) described herein, and the one or more microparticles disposed within the core.
  • the compounds are disposed within a matrix (which may be or make up a microparticle, or a “core” as described above), e.g., a wax matrix, a polyethylene oxide matrix, hydroxypropyl methyl cellulose, and others that are known in the art.
  • matrices, microparticles, outer layers and cores are preferably biodegradable.
  • compositions disclosed herein are administered in vivo by any suitable route including but not limited to: inoculation or injection (e.g. intravenous, intraperitoneal, intramuscular, subcutaneous, intra-aural, intraarticular, intramammary, and the like), topical application (e.g. on areas such as eyes, skin, in ears or on afflictions such as wounds and burns) and by absorption through epithelial or mucocutaneous linings (e.g., nasal, oral, vaginal, rectal, gastrointestinal mucosa, and the like).
  • suitable means include but are not limited to: inhalation (e.g. as a mist or spray), orally (e.g.
  • the mode of administration is oral or by injection.
  • the compounds are administered using any type of dosing regimen that is suitable, generally as determined by a medical professional such as a physician or physician’s assistant.
  • the compounds may be administered from about 1-6 times per day, e.g., about 1, 2, 3, 4, 5, or 6 times per day, or even more frequently, especially in early phases of recovery from surgery, accidents, etc., when administration may be every 2-4 hours.
  • administration is self-administration PRN (as needed) by the patient, e.g., using a self-dosing pump.
  • administration may be daily, or every 2, 3, 4, 5, or 6 days, or weekly, or every 7-10 days, or biweekly, or monthly.
  • a single dose is generally about 0.05 mg, 0.1 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 20 mg, 23 mg, 24 mg, 25 mg, 26 mg or 30 mg of the compound or more, including all decimal fractions in between these values, such as 4.1, 4.2, 4.3...4.8, 4.9, 5.0, for example.
  • a single dose is about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 100 mg or more, such as about 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000 (or more, e.g., up to about 1500 or 2000 mg per dose) including all integers in between these values, such as 30, 31, 32, 33, 34, 35 and 125, 126, 127...148, 149, 150, as examples.
  • compositions may be administered in conjunction with other treatment modalities such as substances that boost the immune system, various chemotherapeutic agents, antibiotic agents, other analgesic agents, and the like, or activities such as exercise, counseling, psychiatric care, electronic nerve signal blocking, etc.
  • treatment modalities such as substances that boost the immune system, various chemotherapeutic agents, antibiotic agents, other analgesic agents, and the like, or activities such as exercise, counseling, psychiatric care, electronic nerve signal blocking, etc.
  • R 1 is H or OH
  • R 2 is H or CH3
  • Administration of the compounds advantageously does not cause addiction thereto.
  • the compounds disclosed herein provide pain relief to subjects in need thereof, without the risk of addiction. As such, they replace current addictive opioid medicaments such as morphine and heroin.
  • patients with acute and/or chronic pain conditions are treated with the compounds, the conditions including but not limited to: acute pain, chronic pain, migraine, other headache disorders, osteoarthritis, diabetic neuropathy, chemotherapy -induced neuropathy, sickle-cell pain, post stroke pain, post-operative pain, pain during healing of scars, pain caused by burns, pain caused by spinal injury or disease, pain caused by broken bones and/or lacerations, pain during childbirth, and pain related to other neurological disorders, e.g. multiple sclerosis, opioid misuse, stimulant misuse, and the like.
  • Administration of the compounds may be used to treat existing pain or to prevent the occurrence of pain.
  • pain may exist as a result of an accident or surgery or disease and administration of the compounds treats (eliminates of lessens) the level of pain.
  • the compounds can be administered to prevent the occurrence, or at least lessen, the level of pain when it would otherwise occur.
  • a preferred outcome of administration of the disclosed compounds is complete elimination of pain
  • much benefit can accrue without complete elimination but with simply lessening the level of pain to a tolerable level, e.g., a level at which the treated person is able to conduct daily activities, sleep comfortably, engage in physical therapy, engage in social activities, etc., to the best of his/her ability.
  • a tolerable level e.g., a level at which the treated person is able to conduct daily activities, sleep comfortably, engage in physical therapy, engage in social activities, etc.
  • the present compounds are employed to “wean” persons addicted to an addictive narcotic from that drug to a compound disclosed herein.
  • the person may or may not be in need of pain relief but is in any case dependent on the use of a narcotic to avoid and/or lessen symptoms of narcotic addiction.
  • the addictive substance may be administered at a normal dose together with a small amount of a compound described herein, and over a period of time (e.g., several days or a week, or more), the amount of the addictive drug is decreased and the amount of the non-addictive compound disclosed herein is increased until the addictive drug can be eliminated with a minimum of side effects for the subject.
  • narcotic tolerance and/or addiction that can be eliminated or lessened (decreased) include but are not limited to dysphoria, psychomimetisis, seizures, altered renal function, etc.
  • Side effects of withdrawal from narcotics that can be eliminated of lessened (decreased) include but are not limited to muscle pain or aches, hunger or loss of appetite, fatigue, sweating, cravings, nausea, fever and/or chills, tremors, vivid dreams, flu-like symptoms, sweating, heart palpitations, and/or psychological withdrawal symptoms such as violent mood swings, anxiety and depression.
  • NMF an analgesic agent
  • Characterizations including primary in vitro ADMET studies (hERG toxicity, plasma protein binding, permeability and hepatic metabolism), and in vivo pharmacodynamic and toxicity profiling (time course, abuse liability, tolerance, withdrawal, respiratory depression, body weight, and locomotor activity) are described in this Example.
  • naltrexone was provided by NIDA, and 3-dehydroxy naltrexone was synthesized from naltrexone via activation and hydrogenation following the reported methods (Scheme 1) (Musliner, W. J. et al. J. Am. Chem. Soc. 1966, 88 (18), 4271-4273).
  • the stereoselectivity was introduced by either Noyori catalysts (f, j, Scheme 1), which required no chiral ligands in this case, or a conformation-induced-steric -hindrance method (c-d, g-h, k-1, Scheme 1).
  • Noyori catalysts f, j, Scheme 1
  • a conformation-induced-steric -hindrance method c-d, g-h, k-1, Scheme 1
  • the method using asymmetric catalysts has advantages including simple one-step setup, higher yields, and carcinogen-free.
  • the conformation-induced- steric- hindrance method (c-e) is more time-efficient for obtaining compounds 1 or 5.
  • Radioligand competitive binding assays are frequently performed to determine the binding affinity and selectivity of potential GPCR ligands.
  • the binding affinity of the target compounds were determined based on their ability to compete and replace the corresponding radioligands at each receptor.
  • 3 -dehydroxylation on the epoxymorphinan skeleton may diminish MOR and DOR affinity, but not that of KOR, which could help enhance the selectivity for the KOR over both the MOR and DOR (Table 1).
  • iV-Methylation might be beneficial to KOR affinity but not to DOR binding.
  • Functional assays are usually performed to determine the efficacy and potency of GPCR ligands.
  • [ 35 S]-GTPyS binding assay and calcium mobilization (flux) assay are two common and established functional assays used for evaluating opioid receptor ligands.
  • the [ 35 S]-GTPyS assay is applied to test the direct activation on a receptor level, the activation of which by the GPCR can be quantified by measuring the amount of the radiolabeled GTP analog bound to the cell membrane.
  • compound 9 to 16 all acted as high-efficacy KOR agonists and seven out of eight were observed with > 90% efficacy.
  • compound 10, 11 and 12 are the most potent agonists with subnanomolar EC50 values.
  • compound 11 possessed picomolar level potency in the [ 35 S]-GTPyS assay, almost four times more potent than NFU (12).
  • Compounds 9, 14, 15, and 16 possessed single-to-double-digit nanomolar high potency, while the EC50 of 13 is at three-digit nanomolar level.
  • each compound was injected systemically (s.c.) to a group of six mice. After 20 minutes, the tail flick response times were determined. The longer duration their tails stayed in water before flicking, the higher antinociceptive effects the compound possessed. The antinociceptive effect was quantified using %MPE.
  • NMF neuropeptide 11
  • a KOR/DOR dual activating mechanism may play a major role in its antinociception potency.
  • NMF was selected for further pharmacology and pharmacokinetics characterizations.
  • In vivo selectivity study was first carried out to verify the proposed KOR/DOR dual activation mechanism of the antinociceptive effects of NMF. Therefore, KOR-selective antagonist nor-BNI, DOR- selective antagonist NTI, and MOR-selective irreversible antagonist >-FNA were co- administered with NMF in warm-water tail immersion assays, respectively.
  • NFU showed 3-4 hours action time at 0.003 mg/kg in AA-induced abdominal constriction, less than 2 hours at 0.03 mg/kg in a hot plate studies, and about 1.5 hours at 0.1 nmol (i.t.) in warm water tail withdrawal studies.
  • fentanyl functioned as a reinforcer and 3.2 pg/kg/infusion fentanyl maintained significantly higher rates of responding than saline.
  • the present fentanyl results are consistent with previous results demonstrating intravenous fentanyl self-administration in rats.
  • no NMF dose across a 100-fold range, reinforced the responding rates in rats.
  • the effective analgesic doses of NMF in rats remain to be examined, the current results have further supported the low efficacy of NMF at the MOR in vivo, as concluded from the in vitro and in vivo studies. More importantly, as a non-reinforcer in rats, NMF would be predicted to have low-to-no abuse liability.
  • NLX-precipitated withdrawal symptoms include wet dog shakes, paw tremors, jumps, and diarrhea.
  • the mice who received 0.1 mg/kg, a dose resulting in maximum antinociception in the same mice, of NMF twice daily for consecutive four days showed no withdrawal symptoms at all after challenged with 1 mg/kg NLX.
  • the mice in the 0.5 mg/kg NMF group exhibited no jumps or signs of diarrhea after NLX challenge.
  • NMF neuropeptide
  • hERG K V 11.1
  • a subunit of a potassium channel can potentially prolong QT-interval and lead to a fatal tachyarrhythmia.
  • the inhibition of tail current from a series of concentrations of NMF and a reference compound, E-4031 were tested concurrently using CH0-K1 cell line.
  • the IC50 of E-4031 was 18 nM and NMF 6.7 pM, respectively. Taking the extraordinary analgesic potency into consideration, NMF is not likely to cause cardiac toxicity by blocking hERG when administered at therapeutic doses.
  • Plasma protein binding plays a significant role not only in chemical-induced toxicity but also in modulating drug concentration at the target sites, thereby influencing the in vivo efficacy.
  • the ti/2-determining parameters, Cl and Vd, are also partially dependent on PPB. Therefore, PPB assessment is a necessary routine study in drug discovery and development. Additionally, interspecies difference in PPB, although not common, is sometimes encountered.
  • the PPB of NMF was tested using both human and rat plasma. NMF exhibited 68% and 76% PPB in human plasma and rat plasma, respectively (Table 4). Both PPBs were higher than those of morphine, but very much lower than alkaloids such as mitragynine and speciociliatine, which also function as opioid agonists and show 90-99% PPB.
  • In vitro caco-2 permeability assay is a commonly used and accepted surrogate for predicting human intestinal absorption.
  • a compound with a greater-than-lOxlO -6 cm/s P app has been conventionally considered as highly permeable, but the criteria and experiment condition are inconsistent through the literature.
  • NMF showed a secretive transport permeability of 31.8 xlO -6 cm/s, yielding an efflux ratio of 3.1.
  • the efflux transport may pose a barrier for intestinal permeability, however according to the empirical rules summarized by Wang, J., et al. (Skolnik, J. W., Current Topics in Medicinal Chemistry. 2013, pp 1308-1316), this efflux ratio should not be a significant risk for reduced permeability.
  • NTX Naltrexone
  • Other reagents were purchased from commercial vendors (such as Sigma- Aldrich and Aidlab Chemicals) and used without further purification. Flash column chromatography was performed with silica gel columns (230-400 mesh, Merck). ’H (400 MHz) and 13 C (100 MHz) nuclear magnetic resonance (NMR) spectra were recorded with tetramethylsilane as the internal standard on a Bruker Ultrashield 400 Plus spectrometer. High resolution mass spectroscopy (HRMS) was performed on an Applied Bio Systems 3200 Q trap with a turbo V source for TurbolonSpray.
  • HRMS high resolution mass spectroscopy
  • HPLC analysis was done with a Varian ProStar 210 system on Microsorb-MV 100-5 C8/C18 column (250 mm x 4.6 mm) at 254 nm, eluting with acetonitrile/water (0.1% TFA) (85/15) at 1 mL/min over 30 min. Melting points were determined using OptiMelt automated melting point system (Fisher Scientific).
  • reaction mixture was cooled down to r.t., 20 mL anhydrous EtOH and 2 g 4 A MS were added and stirred for 5 min. Then NaBIL (117 mg, 3.1 mmol) was added and the reaction mixture was allowed to stir at r.t. overnight. The reaction mixture was filtered through celite and the filtrate was concentrated. Then the residue was washed with H2O and extracted with DCM (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated.
  • the pH of the reaction mixture was adjusted to approximately 2 using 0.4 mL concentrated hydrochloride. Then 10% palladium on carbon (62 mg) was transferred to the bottle and shaken well. Then the bottle was set on hydrogenator at r.t. and ran for 23 h. Then the catalyst was filtered off through celite and the filtrate was concentrated as the crude product. Cold mixture of methanol and isopropanol (1:9) was used to crystallize and light yellow powder was obtained (90 mg, 0.2 mmol, yield 43%).
  • the pH of the reaction mixture was adjusted to approximately 2 using 0.4 mL concentrated hydrochloride. Then, the catalyst, 10% palladium on carbon (200 mg), was transferred to the bottle and shaken well. After the bottle was set on Parr hydrogenator under 60 psi, the hydrogenation reaction was allowed to run at r.t. for three days. Then the catalysts were filtered off and the filtrate was concentrated to a yellow oil. A mixture of methanol and isopropanol (1:9 or 1:10) was used to recrystallize and yield a pure product (2, 210 mg, 0.5 mmol, yield 66%).
  • Noyori catalyst method Naltrexone (168 mg, 0.5 mmol) and methylamine hydrochloride (139 mg, 1.8 mmol) were added to a round-bottom flask with 1.3 mL anhydrous acetonitrile and stirred for 15 min. Anhydrous triethylamine (0.7 mL) was added dropwise followed by the addition of 0.4 mL formic acid. Dichloro(p-cymene)Ru(II)dimer (3 mg) was then dissolved in 0.5 mL anhydrous acetonitrile and added.
  • reaction mixture was cooled down to r.t.. After 20 mL fresh anhydrous EtOH and 2.2 g 4A MS were added and stirred for 5 min, NaCNBHa (140 mg, 2.2 mmol) was added and the reaction was allowed to stir at r.t. overnight.
  • NaCNBHa 140 mg, 2.2 mmol
  • reaction mixture was first filtered through celite and the filtrate was concentrated in vacuo. The residue was washed with H2O and extracted with DCM (6 x 50 mL). Then, the combined organic layers were dried over sodium sulfate and concentrated to a dark yellow oil.
  • the filter papers containing filtered samples were then transferred into the scintillation vials filled with 4 mL of scintillation fluid. After 9 h, the samples were quantified using the liquid scintillation counter. Competition for bound radioligand was calculated using nonlinear regression analysis to determine the IC50 values with GraphPad 6.0 software. The Ki values were determined from the IC50 values using the Cheng-Prusoff equation. The assay was performed in duplicates and repeated at least three times.
  • [ 35 S]-GTPyS binding assay 10 pg of mMOR-CHO, mKOR-CHO or mDOR-CHO membrane protein was incubated with 20 pM GDP, 0.1 nM [ 35 S]-GTPyS, assay buffer (TME + 100 mM NaCl), and varying concentrations of the testing compounds for 90 min in a 30 °C water bath. Nonspecific binding was determined with 20 pM unlabeled GTPyS. 3 pM DAMGO, 5 pM U50,488H or 5 pM SNC80 was included as maximally effective concentration of a full agonist for the MOR, KOR or DOR, respectively. Assay buffer was used for all the dilutions.
  • Percent DAMGO/U50,488H/SNC80-stimulated [ 35 S]-GTPyS binding was defined as (net- stimulated binding by ligand/net- stimulated binding by 3 pM DAMGO/5 pM U50,488H/5 pM SNC80) x 100.
  • the normalized data were subjected to nonlinear regression analysis to determine EC50 and E m ax values using GraphPad 6.0 software.
  • hERG toxicity study was performed in CHO-K1 cell line.
  • the degree of inhibition (%) was obtained by measuring the tail current amplitude, which is induced by a one second test pulse to -40 mV after a two second pulse to +20 mV, before and after drug incubation (the difference current was normalized to the control).
  • Concentration (log) response curves were fitted to a logistic equation (three parameters assuming complete block of the current at very high test compound concentrations) to generate estimates of the 50% inhibitory concentration (IC50).
  • the concentration response relationship of the test compound was constructed from the percentage reductions of current amplitude by sequential concentrations.
  • Dialysis membranes were soaked in DI water, 30% ethanol and isotonic sodium phosphate buffer subsequently.
  • Plasma was obtained by centrifuge from fresh blood.
  • the dialysate side of the 96-well dialysis apparatus was loaded with 0.15 mL of phosphate buffer (0.05 M sodium phosphate in 0.07 M NaCl, pH 7.5).
  • the same volume of plasma spiked with 10 mM test compound was pipetted into the sample side.
  • After 8 h incubation at 37 °C, post-dialysis plasma and buffer volumes were recorded and 90 mL of phosphate buffer was added to every 10 mL of plasma, and then precipitated with two volumes of acetonitrile.
  • the quantification data was collected using LC-MS and calculated as following:
  • Hepatic metabolism S9 fraction incubation 0.1 pM of NMF or reference compounds was tested in human liver S9 plus 1 mM UDPGA or rat liver S9 plus 1 mM UDPGA, respectively.
  • concentration of each compound was determined using LC-MS.
  • metabolic stability expressed as percent of the parent compound remaining, was calculated by comparing the peak area of the compound at the time point relative to that at time 0.
  • the half-life (T1/2) was estimated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) vs. time, assuming the first-order kinetics. In Vivo Studies. Animals.
  • mice 5-8 Week 25-35 g male Swiss Webster mice (Envigo Laboratories, Frederick, MD, USA) were housed in cages (5 maximal per cage) in animal care quarters and maintained at 22 ⁇ 2 °C on a 12 h light-dark cycle, except for the mice used for respiration measurement who were maintained in the reversed light-dark cycle. Food (standard chow) and water were available ad libitum. The mice were brought to the lab (22 ⁇ 2 °C, 12 h light/dark cycle) and allowed 18 h to recover from transport. All studies used at least six mice for each group, and withdrawal studies were performed in the respective mice that were used in tolerance studies.
  • Rats A total of 10 rats (5 males and 5 females) Sprague- Dawley rats were acquired at approximately 8-10 weeks of age (Envigo Laboratories, Frederick, MD, USA) and surgically implanted with custom-made jugular catheters and vascular access ports (Instech, Plymouth Meeting, PA, USA) as described in detail elsewhere. Rats were singly housed in a temperature and humidity-controlled vivarium that was maintained on a 12 h light/dark cycle. Water and food (Teklad Rat Diet, Envigo) were provided ad libitum in the home cage. Protocols and procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at Virginia Commonwealth University Medical Center and comply with the recommendations of the IASP (International Association for the Study of Pain).
  • IACUC Institutional Animal Care and Use Committee
  • the tail-flick test was performed using a water bath with the temperature maintained at 56 ⁇ 0.1 °C. The distal one-third of the tail was immersed perpendicularly in water, and the mouse rapidly flicked the tail from the bath at the first sign of discomfort. The duration of time the tail remained in the water bath was counted as the baseline latency. Untreated mice with baseline latency ranging from 2 to 4 seconds were used. Test latency was obtained 20 min later after injection (s.c.). A 10-second maximum cutoff latency was used to prevent any tissue damage.
  • %MPE percentage of maximal possible effect
  • Heroin hydrochloride and fentanyl hydrochloride were provided by the National Institute on Drug Abuse Drug Supply Program (Bethesda, MD). Modular operant chambers located in sound-attenuating cubicles (Med Associates, St. Albans, VT) were equipped with two retractable levers and LED lights. Intravenous (i.v.) compound solutions were delivered as described previously elsewhere. After each behavioral session, catheters were flushed with gentamicin (0.4 mg) and catheter patency was verified at the end of each experiment by instantaneous muscle tone loss following methohexital (0.5 mg) administration. Rats were initially trained to respond for i.v.
  • saline was substituted for heroin every other session (i.e., SDSDS; S, saline; D, drug) until the number of saline infusions earned was at least 75% lower than the number of heroin infusions earned during the preceding heroin session for two consecutive alternations.
  • the same experimental program was utilized during the saline substitution sessions, using the same infusion duration as a 32 pg/kg/infusion of heroin of 5 s per 300g of rat weight.
  • test sessions were inserted into the sequence (i.e., DTSTD or STDTS; T, test) to evaluate responses over a range of NMF doses (1-100 pg/kg/infusion).
  • Fentanyl doses (0.32-10 pg/kg/infusion) were also determined as a positive control. Saline and each unit NMF and fentanyl dose was tested once in each rat using a counterbalanced dosing order. The primary dependent measure for the NMF and fentanyl self-administration studies was the number of infusions earned per session and these data were plotted as a function of drug dose. Data were analyzed using a one-way repeated-measures ANOVA followed with Dunnet’s post-hoc tests using Prism 9.0 software.
  • Toxicity, tolerance and cross tolerance Vehicle, 0.1 mg/kg NMF, 0.5 mg/kg NMF, and 10 mg/kg morphine was given (s.c.) to four groups of mice twice a day. Weight was measured before drug administration every day and warm water tail immersion was performed to each mouse 20 min after the first injection in the day. On day 5, vehicle, 10 mg/kg morphine, and 0.1 mg/kg NMF, were given to the mice who received morphine injections for 4 days continuously, respectively. Then cross tolerance was evaluated using warm water tail immersion experiment. Weight change and tolerance data were analyzed using t-test, i.e., data collected from day 2-4 was compared to day 1, and cross tolerance data was analyzed using one-way ANOVA followed with Dunnet’s post-hoc tests using Prism 8.0 software.
  • mice 75 mg morphine pellets were implanted as described previously elsewhere. In brief, mice were anesthetized with 2.5% isoflurane, neck was shaved and cleaned with povidone-iodine, and then a 1-cm horizontal incision was made at the base of the neck. A 75-mg morphine pellet was inserted in the space before closing the site with Clay Adams Brand, MikRon AutoClip 9-mm wound clips (BD Diagnostics, Sparks, MD). The animals were allowed to recover in their home cages where they remained throughout the experiment. NMF-dependent mice: 0.1 mg/kg NMF or 0.5 mg/kg NMF was given subcutaneously to mice every 12 hours for four consecutive days.
  • Locomotor activities.Activity chambers (Med Associates, St. Albans, VT) were used for locomotor activity study. Each individual chamber has closeable doors and a ventilation system.
  • the interior of the chamber consists of a 27 x 27 cm Plexiglas enclosure that is wired with photo-beam cells connected to a computer console that counts the activity of the animal. Mice were habituated to the chamber for 20 minutes 24 h before the experiment. On the day of experiment, mice were injected with a desired dose of the compound subcutaneously and placed in the chambers immediately. Ambulatory counts, jumps, distance traveled, and average speed were monitored and recorded for 30 minutes. Data were analyzed using a oneway repeated-measures ANOVA followed with Dunnet’s post-hoc tests using Prism 9.0 software.
  • CHO Chinese hamster ovary
  • CL clearance
  • CNS central nervous system
  • DDI drug-drug interaction
  • DOR delta opioid receptor
  • FDA Food and Drug Administration
  • KOR kappa opioid receptor
  • MOR mu opioid receptor
  • MPE maximum possible effects
  • P app apparent permeability coefficient
  • PD pharmacodynamics
  • PK pharmacokinetics
  • PPB plasma protein binding
  • Vd volume of distribution.
  • nalfurafine s structure-activity relationships were systematically studied through the design, synthesis, and evaluation of twenty-four analogs.
  • Rational molecular design was conducted with NLF as the lead resulting in 64 designed ligands.
  • the design was based around variation of five key components of the NLF molecular structure (Figure 13.) 1) Compounds either maintain or lack the 3-hydroxy group present on NLF. This functional group may be crucial for recognition of binding sites of different opioid receptors, and combined with the C6 conformation may govern selectivity, as demonstrated by us and others. 2) Compounds vary in their conformational arrangement, taking either the 6a or 6P isomeric form; this may test for a more favorable selectivity profile. 3) The amide nitrogen atom is secondary or tertiary via presence of a methyl group. This may verify whether the N-methyl is important for KOR agonist activity.
  • the linker between the furan and amide carbon atoms is either conjugated via a trans double bond or saturated (i.e., single bond). This enables assessment of the degree of rigidity that is tolerated and/or flexibility that is needed for binding.
  • the furan ring attachment point is varied between the 2’ and 3’ position; this variation probes the binding pocket for the optimal binding interaction.
  • Syntheses of the 24 designed ligands contain multiple divergent and convergent methods as depicted in Figure 15. If the final compound will not bear a 3-hydroxyl group, 3 -dehy doxy naltrexone must first be synthesized.
  • Naltrexone and 3-dehydoxynaltrexone as the two starting materials containing the classical epoxymorphinan skeleton, were then subjected to four different reductive amination methods to yield eight different naltrexamines: namely, 6a-naltrexamine, 6a-3-dehydroxynaltrexamine, 6P-naltrexamine, 6P-3-dehydroxynaltrexamine, 6a-N-methyl-naltrexamine, 6a-N-methyl-3- dehydroxynaltrexamine, 6P-N-methyl-naltrexamine, and 6P-N-methyl-3- dehydroxynaltrexamine.
  • Primary amines were then directly coupled to carboxylic acids.
  • the Advanced Chemistry Development Inc. (ACD) Percepta® software was used to predict the physiochemical properties (e.g., cLogP, cpKa, cLogD and TPSA) of designed ligands to assess their drug-likeness.
  • This software aids in screening of compounds using generally accepted guidelines for drug discovery such as Lipinski’s rule of five for oral bioavailability.
  • This rule of five postulates that ligands should have a LogP less than five, less than five hydrogen bond donors, less than ten hydrogen bond acceptors, and a molecular weight less than 500 g/mol. According to Table 6, the designed ligands meet all of these criteria.
  • LogP describes the partition coefficient of uncharged molecules
  • LogD is calculated at a specific pH (often the physiological pH of 7.4) to account for ionizable molecules.
  • the optimal LogD for drug molecules may be between 1-3, and all of the compounds fall within this range.
  • base pKa values must fall below 10.5 which is demonstrated in the results that are further supportive of potential for oral delivery as pKa values between 2-3 and 7-8 are promising for absorption in the stomach and intestines, respectively.
  • TPSA is a predictor of drug absorption with values over 140 A indicating poor absorption which these compounds are not subject to.
  • Mol. Wt. Molecular weight (g/mol); cLogP: calculated partition coefficient; cLogD: calculated distribution constant (at physiological pH); cpKa: calculated negative logarithm of the acid dissociation constant; HBD: hydrogen bond donors; HBA: hydrogen bond acceptors; TPSA: topological polar surface area
  • binding affinity is weaker than the other 3-OH compounds when the amide bears 3-OH, is secondary, and is of P conformation and stronger when it bears 3- OH, -CH3, and a conformation. Additionally, there is no apparent effect of the methyl group, the a/p configuration, or the R3 sidechain on KOR or MOR binding affinity while P isomers seemed to have decreased DOR binding affinity (Table 7).
  • the [35S]-GTPyS -binding assay is a functional assay used to assess the in vitro potency and efficacy of synthesized ligands.
  • [ 35 S]-GTPyS binding assays were used to determine whether ligands function as agonists, partial agonists, antagonists, or inverse agonists for the KOR, MOR, and DOR. Their efficacy was related to that of the respective full agonist control following previously established protocol. As displayed in Table 8, most synthesized ligands are full KOR agonists with partial MOR agonism and a range of DOR agonism. More specifically, all compounds have KOR efficacy >80% except compound 2, and all compounds have MOR efficacy ⁇ 40% except compounds 8 and 16. Compounds that have DOR efficacy >80% include 2, 10, 17, 19, 20, 21 and 23 (NCF).
  • Warm-water tail immersion (WWTI) assays are often employed to rapidly characterize opioid receptor ligands; this is a technique that we have used for many years. Briefly, to assess potential antinociception, an animal’s tail (in this case a mouse) is dipped into a warm-water bath. The mouse then flicks its tail to remove the thermal stimulus. This establishes a baseline latency for withdrawal. Administration of synthesized ligands as pretreatments allows determination of whether the compound has agonist activity similar to known control agonists (single-dose agonism paradigm) while pretreatment to known agonists allows determination of potential antagonist effects (single-dose antagonism paradigm) similar to that of known control antagonists. These assays elucidate information about in vivo functional activity, potency, time course, and opioid receptor involvement.
  • a WWTI assay using the single-dose agonism protocol was used as a preliminary in vivo screen.
  • morphine as a positive control, standardly shows a maximum possible effect (MPE) of 100% indicating that the mouse’s tail remained in the warm-water bath for the maximal amount of time (10 s).
  • Figure 16 shows that the MPE elicited by a single dose of 10 mg/kg in the WWTI assay varied greatly by test compound with the results divided into categories based on MPE values.
  • antinociceptive effects indicated here cannot be interpreted as compounds acting as partial agonists because their response in this assay is dose-dependent and dose was not an independent variable, these compounds may simply be less potent.
  • compounds with MPEs from 80-100% include 1, 7, 13, 15, 17, 21, 22, 23 (NCF), and 24. This is mainly in agreement with the most promising compounds identified by the in vitro binding assay which were 1, 5, 7, 8, 13, 15, 16, 21, 23 [NCF], and 24 (overlapping compounds underlined).
  • the single-dose agonism paradigm of the WWTI assay was also used to determine the in vivo potency of the synthesized ligands that displayed MPEs between 80-100% in the single-dose agonism screen.
  • the dose of the novel ligand given as a pretreatment was an independent variable rather than a fixed dose.
  • Table 9 shows that the test compounds have roughly a 1,000-fold range of in vivo potencies. Further, all but two compounds (17 and 22) were more potent than morphine of which six compounds had potencies ⁇ 1 mg/kg while one compound (23 [NCF]) is approximately equipotent to fentanyl. Finally, compounds 21 and 23 (NCF) are approximately equipotent to more potent than NLF.
  • Step 3 Time Course To determine the time course of the synthesized ligands in the WWTI assay, the singledose agonism paradigm was used wherein the ligand is administered s.c. one time and the time lapse in relation to the injection is an independent variable following published protocol. Shown in Figure 17, 0.1 mg/kg NLF resulted in significant antinociceptive effects immediately after injection that lasted for 1 h and were significant once more 4 h post- injection with a return to baseline 9 h post-injection. This is consistent with previous studies which showed: 1) an onset of sedative effects 10 min post i.v.
  • NLF intracranial self-stimulation
  • the WWTI assay was additionally used to assess which opioid receptors are responsible for the in vivo effects of ligands.
  • the receptor selectivity study is a modification of the single-dose antagonism paradigm wherein known selective opioid receptor antagonists are pretreatments to synthesized ligands following previously published protocol. More specifically, the selective and irreversible MOR antagonist P-funaltrexamine (P-FNA), the selective KOR antagonist nor-binaltorphimine (nor-BNI), and the selective DOR antagonist naltrindole (NTI) were used. These compounds at these doses would be hypothesized to inhibit the antinociceptive effects mediated by their respective receptors in the WWTI assay.
  • P-FNA P-funaltrexamine
  • nor-BNI selective KOR antagonist nor-binaltorphimine
  • NTI selective DOR antagonist naltrindole
  • Figure 18 shows that the MPE of NLF is significantly decreased by both NTI and nor- BNI indicating DOR and KOR involvement, respectively.
  • the combination of NTI and nor-BNI pretreatment did not result in a more drastic decrease than either antagonist alone.
  • the selectivity of NLF at the opioid receptors has been previously assessed and was repeated herein as an internal control to ensure alignment with previously reported data.
  • 10 mg/kg nor-BNI s.c. pretreatment antagonized the sedative and antinociceptive effects of low dose (0.01 mg/kg) but not high dose (0.03 mg/kg) NLF and 20 mg/kg nor-BNI s.c.
  • compound 21 the antinociceptive effects are antagonized by both nor-BNI and NTI while pretreatment with both nor-BNI and NTI seems to compound the decrease in compound 21 MPE. This indicates that the in vivo effects of compound 21 are primarily KOR and DOR mediated.
  • Compound 23 (NCF) on the other hand is antagonized by NTI but shows only a slight, non-significant decrease in antinociception with nor-BNI pretreatment while pretreatment with both NTI and nor-BNI seems to compound antagonistic effects. This result that 10 mg/kg s.c.
  • nor-BNI is not effective at antagonizing antinociceptive effects of a higher dose of compound 23 (NCF; 0.1 mg/kg) seems to be in agreement with the previously discussed finding for NLF performed in monkeys. Additionally, these results are in agreement with a previous study on a structurally related compound.
  • mice followed the testing schedule shown in Figure20A. In brief, the day prior to testing, mice were placed in the open field chamber for acclimation. On test day, they were injected with the synthesized ligand or vehicle (double-distilled water, negative control) and immediately placed back into the open field chamber. Photo beam breaks then record the mouse’s locomotion over a 30 min test period.
  • Figure 20B-E shows the distance travelled (cm), ambulatory counts, vertical counts and average speed (cm/s) during the acclimation period of the locomotor activity assay while Figure 20F-I displays these same endpoints after compound injection.
  • distances, counts and speed are reduced in the testing sessions as compared to their corresponding acclimation periods. This is attributable to the novelty-induced hyperlocomotion of the open field chamber during the acclimation period as expected.
  • NLF locomotor activity with compound 23
  • high variance in the compound 21 group across all endpoints both in the acclimation period and after compound administration makes it hard to conclude that this compound does not have any effects on locomotion; this is similar to a previously reported structurally related compound.
  • the novel ligand (or fentanyl at different doses as a positive control) was inserted into the rotation as “test days”. Behavioral sessions occurred daily, in 2 h blocks from approximately 9:30 AM - 11:30 AM.
  • the potential for the development of tolerance is a liability for pain medications, particularly those that are opioidergic.
  • an assay was used to assess the potential for the development of tolerance with chronic treatment of the synthesized ligands.
  • the synthesized ligands as well as morphine (positive control) and vehicle (negative control) were administered two times per day for four days with injections spaced 12 h apart. Efficacy was assessed after the second injection of the day using the WWTI assay.
  • Morphine is known to result in tolerance due its effects at the MOR, it is hypothesized that administration of a ligand with a distinct mechanism of action to mice that are morphine- tolerant may result in a return of antinociceptive effects.
  • mice were injected with the synthesized ligand or morphine positive control two times per day for four days with injections spaced 12 h apart to potentially result in dependence on the ligand.
  • NLF neuropeptide
  • Figure 25A-F shows that compounds 21 and 23 (NCF) were present in the plasma as early as 5 min after their s.c. injection, at which point the plasma concentration was the highest for both compounds.
  • the brain-to-plasma concentration ratio progressively increased from 5 to 60 min for both compounds 21 and 23 (NCF). This indicates that the compounds not only penetrated the BBB, but also that they were accumulating in the CNS over the time points tested. Additionally, it implies that they were not rapidly effluxed.
  • the initial spike in plasma concentration is expected considering pharmacokinetic principles wherein there is a high plasma concentration initially after injection followed by drug distribution and metabolism.
  • Nalfurafine is an approved antipruritic agent in Japan with additional interesting pharmacological results with regard to pain was chosen as a lead for further optimization through systematic structure-activity relationship (SAR) studies. Modifications to the structure of nalfurafine at five positions yielded a series of twenty-four analogs. These twenty- four analogs were obtained in 5-6 steps each.
  • a locomotor activity assay was used to monitor the potential for sedative side-effects due to KOR agonism in mice; apart from vertical counts when NCF was given at 0.5 mg/kg, there was a non- significant trend for a decrease in locomotor activity as monitored by distance travelled, ambulatory counts, vertical counts, and average speed. Across the dose range tested, compound 21 did not result in the same decrease in locomotor activity seen with NCF. To address this potential for sedation as well as the previously noted limitation of using an escape model, studies may consider further probing the therapeutic window using a model that instead assesses the compound’s ability to alleviate pain-induced depression of normal behaviors. Altogether, compound 21 shows potential as an acute treatment for pain management in patients that are not morphine dependent.
  • Peak multiplicities are abbreviated as singlet, s; doublet, d; triplet, t; quartet, q; pentet, p; and multiplet, m; with two letters next to each other representing the first of the second e.g., dd, doublet of doublets.
  • Mass spectrometry analysis was performed on a PerkinElmer AxION 2 TOF MS. Purity as determined by high pressure liquid chromatography was resolved using a Varian ProStar 210. Melting points were determined using an OptiMelt automated melting point apparatus. Flash column chromatography was performed with silica gel columns (230-400 mesh, Merck).
  • Acid chloride (as previously prepared according to general procedure 1 was dissolved in anhydrous CH2CI2 (2 mL) without further purification and 4 A molecular sieves were added on an ice water bath under N2 atmosphere. The amine (1 equiv.) was added in one portion followed by the dropwise addition of triethylamine (4 equiv.). The reaction was allowed to come to room temperature with stirring. After approximately 3 h it was checked by TLC (30: 1 CH2CI2: MeOH W/NH3 H2O) which revealed completion. The reaction mixture was then filtered through celite and concentrated in vacuo.
  • Carboxylic acid (1.5 equiv.) was dissolved in anhydrous dimethylformamide (2 mL) in a pre-dried 50 mL round-bottom flask and stirred with 4 A molecular sieves overnight to pre-dry.
  • a N2 balloon was added followed by the application of an ice-water bath and the addition of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI, 2 equiv.) and hydroxybenzotriazole (HOBt, 2 equiv. + 20%).
  • Triethylamine (5 equiv.) was then added dropwise and fresh 4 A molecular sieves were added to the reaction.
  • Monoclonal mouse opioid receptor (denoted “m”, mKOR and mMOR) and monoclonal human opioid receptor (denoted “h”, hDOR) stably expressed in Chinese hamster ovary (CHO) cell lines were used. Cell lines heterologously expressed each of the cloned receptors to provide a reliable source of one opioid receptor subtype to be studied. This method also yields a higher receptor density, which provides for optimal signal-to-noise ratios in assays.86 Cell membrane homogenate prepared from these cell lines was used in in vitro assays.
  • a fixed concentration of membrane protein (30 pg) was then incubated with the corresponding radioligand in the presence of varying concentrations of designed compound in TME buffer (50 mM Tris, 3 mM MgCh, and 0.2 mM EGTA, pH 7.7) for 1.5 h at 30°C.
  • the bound radioligand was then separated by filtration using a Brandel harvester to determine total binding.
  • Non-specific binding was determined by adding an excess of unlabeled competitive ligand: 5 pM U50- 488, naltrexone, and SCN80 for the KOR, MOR, and DOR respectively.
  • Specific (i.e., opioid receptor-related) binding was defined as the difference between total binding and non-specific binding.
  • [ 35 S]-GTPyS binding assays were used to determine the functional activity of compounds for the KOR, MOR, and DOR (i.e., agonist, partial agonist, antagonist, or inverse agonist). This was done by defining a compound’ s efficacy in relation to that of the full agonist control for that receptor; that is U-50488, DAMGO, and DPDPE for the KOR, MOR and DOR, respectively.
  • Membrane proteins (10 pg of mKOR-CHO, mMOR-CHO, and hDOR- CHO, in turn) were incubated with GDP (15 pM), [ 35 S]-GTPyS (80 pM), varying concentrations of designed compound, 100 mM NaCl, and TME assay buffer (50 mM Tris- HC1, 3 mM MgCh, 0.2 mM EGTA, pH 7.4) to 500 pL for 1.5 h at 30° C. 10 pM of unlabeled GTPyS was used to determine non-specific binding.
  • GDP 15 pM
  • [ 35 S]-GTPyS 80 pM
  • TME assay buffer 50 mM Tris- HC1, 3 mM MgCh, 0.2 mM EGTA, pH 7.4
  • Emax values were related to their respective full agonists by (net- stimulated binding by ligand/net-stimulated by maximally effective concentration of full agonist) x 100%. All assays were conducted in duplicate and repeated at least three times. Results were reported as mean ⁇ SEM.
  • (-)-Morphine sulfate pentahydrate was purchased from Mallinckrodt (St. Louis, MO) and provided by the National Institute on Drug Abuse Drug Supply Program (Bethesda, MD).
  • (-)-Naltrexone HC1 and naloxone HC1 were purchased from Sigma-Aldrich (St. Louis, MO), norbinaltorphimine di-HCl and naltrindole HC1 were purchased from MedChemExpress (Monmouth Junction, NJ), P-funaltrexamine HC1 was purchased from AABlocks (San Diego, CA). All test compounds synthesized herein were formulated as hydrochloride salts. All known and test compounds were dissolved in double-distilled water and used directly. All drug doses were expressed based on the salt forms listed above and delivered based on individual weights as collected immediately prior to each administration.
  • Fentanyl HC1 was provided by the National Institute on Drug Abuse Drug Supply Program (Bethesda, MD) and dissolved in sterile saline. Nalfurafine HC1, compound 21 and NCF (synthesized herein) were dissolved in sterile saline. All solutions were passed through a 0.22 pm sterile filter (Millex GV, Millipore Sigma, Burlington, MA) before intravenous (IV) administration. All drug doses were expressed based on the salt forms listed above and delivered based on individual weights as collected weekly.
  • %MPE was calculated for each mouse. Data are shown as mean ⁇ SEM. ED50 values were calculated using a least-squares linear regression analysis, followed by the calculation of 95% confidence intervals by the Bliss method. Data were compared using one-way ANOVA as appropriate and a significant ANOVA was followed by a Dunnet’s post hoc test as appropriate. Statistical significance was defined as p ⁇ 0.05.
  • mice in nor-BNI groups received 10 mg/kg nor-BNI SC 24 h prior to 0.1 mg/kg test compound SC injection.
  • Mice in [3-FNA groups received 10 mg/kg [3-FNA SC 24 h prior to 0.1 mg/kg test compound SC injection.
  • Mice in NTI groups received 15 mg/kg NTI SC 30 min prior to 0.1 mg/kg test compound SC injection.
  • Mice in the nor-BNI + NTI groups received both nor-BNI and NTI according to the same dosing schedule as mice in receiving a single compound antagonist. Withdrawal latencies for mice in all groups were acquired 20 min post- test-compound administration.
  • Time-Course Study Baseline tail withdrawal latencies were measured according to the “general” procedure one hour prior to SC administration of test compound. Immediately following injection, withdrawal latencies were remeasured (time point 0). Withdrawal latencies were acquired after the first 30 min and after every h until test compound effects wore off with a maximum of 10 h post injection.
  • mice Baseline tail withdrawal latencies were measured according to the “general” procedure prior to any compound administration. To observe development of tolerance, mice were administered positive control (morphine 10 mg/kg), negative control (vehicle) or test compound SC 2x/day for 4 days with injections spaced 12 h apart. The weight of each mouse was measured prior to every administration. Withdrawal latencies for mice in all groups were acquired 20 min after the second injection of the day. On day 5, to analyze cross-tolerance, separate groups of mice that received morphine injections for 4 days were administered positive control (morphine 10 mg/kg), negative control (vehicle) or test compound SC. Withdrawal latencies for mice in all groups were acquired 20 min post injection.
  • Apparatus Six open field activity chambers (Med Associates, St. Albans, VT) were used in the locomotor activity study. Each chamber is located inside a sound-attenuating cubicle (Med Associates) and is equipped with a ventilation system. The interior of the chamber consists of a 27 x 27 cm plexiglass enclosure wired with photo-beam cells and connected to a computer console that monitors the activity of the animal.
  • mice were acclimated to the activity chambers for a period of 30 min. On the day of the experiment, mice were administered vehicle or test compound SC, placed into the activity chambers immediately and activity was monitored and recorded for a period of 30 min.
  • the primary dependent measures are total 1) distance travelled (cm), 2) ambulatory counts, 3) vertical counts, and 4) average speed (cm/s) within the 30 min session. Data are shown as mean ⁇ SEM. Data were compared using one-way or two-way ANOVA as appropriate and a significant ANOVA was followed by a Dunnet’s post hoc test as appropriate. Statistical significance was defined as p ⁇ 0.05. GPower 3.1.9.7 was used for a post hoc computation of achieved power.
  • Apparatus and Catheter Maintenance Twelve modular operant chambers located within sound-attenuating cubicles were assembled as previously reported.107 Following each behavioral session, intravenous catheters were flushed with 0.1 mL of gentamicin (4 mg/mL) and 0.1 mL of heparinized saline (30 units/mL). Catheter patency was verified at least every two weeks and at the conclusion of the study via instantaneous muscle tone loss precipitated by IV methohexital (0.5 mg) administration.
  • DDSSDDSS double alternation schedule
  • rats were switched to a single alternation schedule (i.e., DSDS) until the number of saline infusions earned was >75% below the number of infusions earned on the drug day preceding it for two consecutive alternations.
  • DSDS single alternation schedule
  • the same program was used to run saline sessions and saline infusion duration was equivalent to a “drug” (3.2 pg/kg/inf) day.
  • the primary dependent measure was the number of infusions earned per session. Data were compared using one-way repeated measures ANOVA and the Geisser- Greenhouse correction was applied as appropriate (Prism 9, GraphPad, La Jolla, CA, USA). A significant ANOVA was followed by a Dunnet’s post hoc test as appropriate. Statistical significance was defined as p ⁇ 0.05.
  • mice were administered control (morphine 10 mg/kg) or test compound SC 2x/day for 4 days with injections spaced 12 h apart.
  • naloxone (1 mg/kg) was administered SC to precipitate withdrawal and mice were individually placed into an open - topped, square, clear plexiglass observation chamber (26 x 26 x 26 cm3) with lines partitioning the bottom into quadrants. Withdrawal signs were monitored for a period of 20 min beginning 3 min post naltrexone injection.
  • Data Analysis The primary dependent measures were the withdrawal signs including 1) number of escape jumps, 2) number of paw tremors, 3) number of wet dog shakes and 4) presence or absence of diarrhea. Data are shown as mean ⁇ SEM. Data were compared using one-way ANOVA as appropriate and a significant ANOVA was followed by a Dunnet’s post hoc test as appropriate. Statistical significance was defined as p ⁇ 0.05.
  • Test compound was administered SC and a group of Swiss Webster mice was euthanized by decapitation at each time point (5, 10, 30, 60 min post injection) allowing brain and blood samples to be harvested. Blood samples were centrifuged for 10 min (15,000 g; 4 °C) to collect plasma. Brain and plasma samples were stored at -80 °C for further analysis.
  • LC/MS Analysis Identification and quantification of test compound in mouse brain and plasma was performed using a modification of a previously described method with an internal standard of naloxone-d5.119 Compounds were extracted from both blood and brain by a liquid/liquid extraction. Briefly, brain tissue samples were homogenized 1-part tissue to 3-parts water. Seven-point calibration curves (10-1000 ng/mL or ng/g) in plasma, drug free control, a negative control without internal standard in plasma and brain, and quality control specimens in plasma and brain (30, 300 and 750 ng/mL or ng/g) were prepared and analyzed with each batch of samples.
  • Naltrexone-d5 was added at 10 ng/mL concentration to aliquots of either 100 pL for blood or 400 pL for brain homogenate to each calibrator, control or specimen except the negative control.
  • 0.5 mL of saturated carbonate/ bicarbonate buffer (1:1, pH 9.5) and 2.0 mL of chloroform:2-propanol (8:2) were added.
  • the samples were then mixed and centrifuged.
  • the top, aqueous, layer was aspirated, and the organic layer was transferred to a clean test tube and evaporated to dryness under nitrogen.
  • the samples were then reconstituted in 80:20 water water and transferred to autosampler vials for analysis.
  • the chromatographic separation of test compounds and naloxone-d5 was accomplished using a Shimadzu Nexera X2 liquid chromatography system and a Zorbax XDB-C18 4.6 x 75 mm, 3.5 pm column (Agilent Technologies, Santa Clara, CA).
  • the mobile phases consisted of A) water with 1 g/L ammonium formate and 0.1% formic acid, and B) methanol. The flow rate was set to 1 mL/min. The mobile phase started with 20% B and was increased to 80% B at 1.0 min and held constant for 1.5 min before returning to 20% B.
  • the system detector was a Sciex 6500 QTRAP system with an lonDrive Turbo V source for TurboIonSpray® (Sciex, Ontario, Canada) that had the curtain gas flow rate set at 30 mL/min and the ion source gases 1 and 2 at 60 mL/min.
  • the source temperature was set at 650°C with an ionspray voltage was 5500 V.
  • the declustering potential was 58 eV.
  • the primary dependent measures are 1) the plasma concentration of the test compound (pg/mL), 2) the brain concentration of the test compound (pg/g), and 3) the brain-to-plasma concentration ratio calculated as [brain]/[plasma]. Concentrations were determined by a linear regression plot based on peak ratios of the calibrators. Data are shown as mean ⁇ SEM. Data were compared using one-way ANOVA as appropriate and a significant ANOVA was followed by a Dunnet’s post hoc test as appropriate. Statistical significance was defined as p ⁇ 0.05.

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Abstract

L'invention concerne des composés analgésiques qui se lient à de multiples récepteurs opioïdes, par exemple, ils se lient à la fois au récepteur opioïde mu (MOR) et au récepteur opioïde kappa (KOR). Les composés sont efficaces pour soulager la douleur sans provoquer d'addiction, et ont ainsi un potentiel d'abus faible ou nul.
PCT/US2023/030810 2022-08-23 2023-08-22 Ligands de récepteurs opioïdes à ciblage multiple utilisés en tant que nouveaux analgésiques avec risque d'abus minimal WO2024044179A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6147084A (en) * 1993-07-19 2000-11-14 Toray Industries, Inc. Brain cell protective agent
US6177438B1 (en) * 1993-07-23 2001-01-23 Toray Industries, Inc. Morphinan derivatives and pharmaceutical use thereof
US9221831B2 (en) * 2010-09-21 2015-12-29 Purdue Pharma, L.P. Buprenorphine analogs
WO2023163969A2 (fr) * 2022-02-22 2023-08-31 Virginia Commonwealth University Dérivés de naltrexamine portant des systèmes cycliques hétérocycliques à 5 chaînons utilisés en tant que modulateurs des récepteurs opioïdes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6147084A (en) * 1993-07-19 2000-11-14 Toray Industries, Inc. Brain cell protective agent
US6177438B1 (en) * 1993-07-23 2001-01-23 Toray Industries, Inc. Morphinan derivatives and pharmaceutical use thereof
US9221831B2 (en) * 2010-09-21 2015-12-29 Purdue Pharma, L.P. Buprenorphine analogs
WO2023163969A2 (fr) * 2022-02-22 2023-08-31 Virginia Commonwealth University Dérivés de naltrexamine portant des systèmes cycliques hétérocycliques à 5 chaînons utilisés en tant que modulateurs des récepteurs opioïdes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM COMPOUND ANONYMOUS : "N-[(4R,4aS,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl]-3-(furan-2-yl)-N-methylpropanamide", XP093145807, retrieved from PUBCHEM *
PAGARE PIYUSHA P., LI MENGCHU, ZHENG YI, KULKARNI ABHISHEK S., OBENG SAMUEL, HUANG BOSHI, RUIZ CHRISTIAN, GILLESPIE JAMES C., MEND: "Design, Synthesis, and Biological Evaluation of NAP Isosteres: A Switch from Peripheral to Central Nervous System Acting Mu-Opioid Receptor Antagonists", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 65, no. 6, 24 March 2022 (2022-03-24), US , pages 5095 - 5112, XP093145809, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.2c00087 *

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