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WO2025171222A1 - Utilisation de phytocannabinoïdes et de leurs analogues en tant que modulateurs allostériques négatifs du récepteur cb1 - Google Patents

Utilisation de phytocannabinoïdes et de leurs analogues en tant que modulateurs allostériques négatifs du récepteur cb1

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Publication number
WO2025171222A1
WO2025171222A1 PCT/US2025/014952 US2025014952W WO2025171222A1 WO 2025171222 A1 WO2025171222 A1 WO 2025171222A1 US 2025014952 W US2025014952 W US 2025014952W WO 2025171222 A1 WO2025171222 A1 WO 2025171222A1
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WO
WIPO (PCT)
Prior art keywords
cancer
thc
cbd
combination
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/014952
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English (en)
Inventor
Amar Gopal Chittiboyina
Pankaj Pandey
Shamba Chatterjee
Ikhlas A. Khan
Robert John DOERKSEN
Ahmed Mohamed Galal OSMAN
Mahmoud Ahmed Elsohly
Ayat Hesham ZAGZOOG
Robert Brad LAPRAIRIE
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.)
University of Saskatchewan
University of Mississippi
Original Assignee
University of Saskatchewan
University of Mississippi
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Application filed by University of Saskatchewan, University of Mississippi filed Critical University of Saskatchewan
Publication of WO2025171222A1 publication Critical patent/WO2025171222A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Cannabis (Cannabis sativa) consumption for medical and recreational purposes is a hotly debated social and political issue that has been increasing dramatically in the public eye within the last decade.
  • the passage of the 2018 Farm Bill on industrial hemp (C. sativa with ⁇ 0.3% tetrahydrocannabinol (THC)) and legalization of medicinal use of Cannabis sativa and its constituents in US states allowed consumers to readily access such materials for the management of pain and other medical symptoms, resulted in a proliferation of cannabis products (e.g., Dronabinol/MarinolTM, Epidiolex).
  • Cannabis contains more than 600 phytoconstituents; among them, -120 constituents are recognized as cannabinoids, and another 120+ compounds as terpenes. Many of these constituents are recognized to have deleterious and/or potential therapeutic effects, which are often mediated through the endogenous cannabinoid system.
  • Cannabinoid receptors are G-protein-coupled receptors (GPCRs), and approximately 35% of Food and Drug Administration-approved small molecules target GPCRs.
  • GPCRs G-protein-coupled receptors
  • Cannabinoid receptors are of two subtypes, CB1 and CB2.
  • CB1 receptors are present in various brain parts and play important roles in rewards, learning, memory, motor control, and addiction.
  • Chronic and acute use of cannabis strains and extracts containing high concentrations of A 9 -THC compared to cannabidiol (CBD) has been associated with numerous neuropsychiatric side effects, including anxiogenic effects, cognitive and memory impairment, and dependence.
  • CB1-positive and negative allosteric modulators PAMs and NAMs, respectively.
  • the binding of a pure NAM to an allosteric site decreases the affinity and/or efficacy of signaling of the orthosteric or endogenous ligand at the orthosteric binding site.
  • a CB1-NAM by reducing endogenous signaling in a spatially- and temporally-controlled fashion, may produce a more optimal spectrum of physiological effects than direct CB1 antagonism, resulting in a more desirable pharmacological profile.
  • Target selectivity and off-target side effects are the two major limiting factors for orthosteric CB1 ligands; therefore, the search for allosteric modulators (AMs) is a widely used drug discovery approach to avoid such limitations.
  • AMs allosteric modulators
  • Emerging clinical and preclinical findings demonstrate that CBD, the major non-psychoactive phytocannabinoid in Cannabis, possesses antipsychotic and anxiolytic properties, while the neuropsychiatric side effects of Cannabis are associated with THC. CBD is believed to mitigate the neuropsychiatric side effects of THC; however, the precise molecular mechanisms are largely unknown. Additionally, CBD has already been established to possess a poor binding affinity with CB1 and CB2 receptors, so researchers believe CBD analogs will unlikely bind more effectively with CB receptors.
  • phytocannabinoids and their analogs offer a potential advantage for developing precision drugs or formulations in combination with THC for many disorders involving CB1 receptors.
  • CBD binds to the CB1 receptor as a negative allosteric modulator (NAM), and only a few synthetics (viz., ORG27569, PSNCBAM-1 , Fenofibrate, and ABM300) and endogenous ligand (viz., pregnenolone) are known to date; these are known to have poor efficacy.
  • NAM negative allosteric modulator
  • the disclosure in one aspect, relates to the use of negative allosteric modulators (NAMs) of cannabinoid receptor 1 (CB1) and pharmaceutical compositions comprising the same in methods of treating or preventing diseases or disorders including substance abuse, anxiety, pain, obesity, cancers, neurodegenerative disorders, and central nervous system (CNS) diseases.
  • NAM negative allosteric modulators
  • CBDP cannabinoid receptor 1
  • the pharmaceutical compositions additionally include A 9 -tetrahydrocannabinol (THC), and the NAMs of CB1 reduce or eliminate unwanted neurological side effects of THC while preserving its disease- and symptom-mitigating effects.
  • FIGs. 1 A-1 D show the in vitro activity of H4-CBD and CBDP. Corresponding analyses are provided in Tables 1 and 2.
  • FIG. 1A shows both H4-CBD and CBDP are not agonists of CB1 compared to the full agonist CP55,940.
  • FIGs. 1B-1C show that adding increasing concentrations of H4-CBD or CBDP results in a concentration-dependent decrease in the potency and efficacy of CB1 signaling by CP55,940 (an orthosteric agonist), consistent with negative allosteric modulation, in Chinese hamster ovary cells (CHO) stably-expressing human CB1.
  • CP55,940 an orthosteric agonist
  • H4-CBD and CBDP The binding affinity of H4-CBD and CBDP to CB1 was measured in membranes from CHO CB1 cells compared to the control compound CP55.940 (an orthosteric agonist) and CBD (a reference for comparison) (FIG 1 D).
  • Mutagenesis of selected amino acids at CB1 receptor altered the competition binding of H4-CBD and CBDP compared to CBD or the orthosteric ligand CP55.940 in the presence of [ 3 H]-SR141716A (FIG 1D).
  • the S401 847 AA mutation augmented H4-CBD binding similar to CBD; whereas F237 446 AA augmented H4-CBD binding and W241 450 AA abolished binding (FIG 1D).
  • the S401 847 AA mutation augmented binding similar to CBD; and W241 450 AA abolished binding, suggesting both CBDP and H4-CBD share similar modes of CB1 interaction (FIG 1 D).
  • FIG. 2 shows the neurobehavioral effects of A 9 -THC, H4-CBD, and their combination on locomotor activity upon intraperitoneal (I.P.) administration to isogenic C57BL/6NHsd mice.
  • I.P. intraperitoneal
  • FIGs. 3A-3B show the neurobehavioral effects of A 9 -THC, H4-CBD, and their combination on (FIG. 3A) hot plate latency and (FIG. 3B) tail flick upon I.P. administration to isogenic C57BL/6NHsd mice.
  • a total of four (i, vehicle; ii, H4-CBD (10 mg/kg); iii, A 9 -THC (10 mg/kg) and iv, H4-CBD + A 9 -THC (10+10 mg/kg, 1 :1 w/w) groups were studied.
  • FIGs. 4A-4B show the neurobehavioral effects of A 9 -THC, H4-CBD, and their combination on (FIG. 4A) catalepsy and (FIG. 4B) body core temperature upon I.P. administration to isogenic C57BL/6NHsd mice.
  • a total of four (i, vehicle; ii, H4-CBD (10 mg/kg); iii, A 9 -THC (10 mg/kg) and iv, H4-CBD+ A 9 -THC (10+10 mg/kg, 1 :1 w/w) groups were studied.
  • FIG. 5 shows an interaction bar plot for the percentage of time with the novel object (learning and impairment effects) associated with a vehicle (blue), H4-CBD (orange), A 9 -THC (gray), and H4-CBD+ A 9 -THC combination (pattern-filled).
  • FIG. 6 shows the neurobehavioral effects of A 9 -THC, CBDP, and their combination on locomotor activity upon I.P. administration to isogenic C57BL/6NHsd mice.
  • a total of four i, vehicle; ii, CBDP (10 mg/kg); iii, A 9 -THC (10 mg/kg) and iv, CBDP + A 9 -THC (10+10 mg/kg, 1 :1 w/w) groups were studied.
  • FIGs. 8A-8B show the neurobehavioral effects of A 9 -THC, CBDP, and their combination on (FIG. 8A) catalepsy and (FIG. 8B) body core temperature upon I.P. administration to isogenic C57BL/6NHsd mice.
  • FIG. 9 shows an interaction bar plot for the percentage of time with the novel object (learning and impairment effects) associated with a vehicle (blue), CBDP (orange), A 9 -THC (gray), and CBDP+ A 9 -THC combination (pattern-filled).
  • the binding site of these NAMs was putatively identified by site-directed mutagenesis experiments involving amino acids S401 847 AA of the intracellular site between TMHs 2, 6 and 7; or F237 446 AA and/or W241 450 AA at the TMH2 and TMH4 cholesterol binding motif (FIG 1D).
  • the in vitro data indicated that the intracellular site (TMH2, TMH6, TMH7, and helix 8) was the most favorable and preferred allosteric site for H4-CBD and CBDP at CB1 R.
  • This study also examined the effects of administering H4-CBD or CBDP intraperitoneally, in combination with A 9 -THC, on measures of locomotor activity, antinociceptive effects, body temperature, catalepsy (i.e. , cannabinoid tetrad), and learning and memory using novel object recognition test in male mice.
  • in vivo testing confirmed that H4-CBD and CBDP mitigate A 9 -THC-induced memory impairment without altering the beneficial biological attributes of A 9 -THC.
  • disclosed herein is the use of these CBD analogs in combination with A 9 -THC to treat obesity, drug abuse, pain and central nervous system (CNS) disorders.
  • X is selected from H, OH, or alkyl; wherein Y is selected from linear or branched alkyl, linear or branched alkenyl, cycloalkyl, cycloalkenyl, alkyl aryl, or alkenyl aryl; wherein C1’-C2’ is dihydro or dehydro; wherein two of Ri a , Ri b , and Ri c are OH, and wherein the Ri a , R , or Ri c that is not OH is selected from C1-C9 linear or branched alkyl or cycloalkyl; C2-C6 ether, ester, amide, or N-alkylamide; or substituted aryl or heteroaryl; or alkylaryl or alkyl heteroaryl; wherein a carbon atom indicated by * has substantially (R) stereochemistry, substantially (S) stereochemistry, or any combination thereof; wherein a carbon atom indicated by ** has substantially (R) stereochemistry, substantially
  • R and Rw are OH and Ri a is selected from C1 -C9 linear or branched alkyl or cycloalkyl; 02-06 ether, ester, amide, or /V-alkyl amide; or substituted aryl or heteroaryl; alkylaryl or alkyl heteroaryl.
  • Ri a and Ri c are OH and R is selected from C1-C9 branched alkyl or cycloalkyl; C2-C6 ether, ester, amide, or N-alkyl amide; or substituted aryl or heteroaryl; alkylaryl or alkyl heteroaryl.
  • the Ri a , Ri b , or Ri c that is not OH is:
  • Z is selected from F, Cl, Br, CN, or NO2; and wherein Q is selected from NH, O, or S.
  • the NAM can be H4-CBD, CBDP, or any combination thereof.
  • the pharmaceutical compositions further include A 9 - tetrahydrocannabinol (A 9 -THC).
  • a 9 -THC A 9 - tetrahydrocannabinol
  • the NAM and the THC are present in a weight ratio of from about 1:0.13 to about 1 :1 , or of about 1 :0.13, 1 :0.3, or 1:1.
  • the pharmaceutical compositions can further include at least one carrier, diluent, or excipient, such as for example, a solvent, emulsifier, surfactant, or any combination thereof.
  • the THC is administered in an amount of from about 1 mg/kg of subject body weight to about 20 mg/kg of subject body weight, or at about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg/kg of subject body weight, or a combination of any of the foregoing values, or a range encompassing any of the foregoing values.
  • the disease or disorder can be selected from obesity, substance abuse, pain, anxiety, cancer, a neurodegenerative disorder, or another central nervous system (CNS) disorder.
  • the cancer can be selected from acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, astrocytoma, basal cell carcinoma, bladder cancer, breast cancer, Burkitt’s lymphoma, carcinoid tumor, cervical cancer, chondroblastoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, cutaneous t-cell lymphoma, endometrial cancer, ependymoma, esophageal cancer, extrahepatic bile duct cancer, gallbladder cancer, glioblastoma, glioma, hairy cell leukemia, head and neck cancer, Hodgkin’s lymphoma, hypopharyngeal cancer, intrao
  • the use of the NAM reduces or eliminates one or more side effects of the THC such as, for example, altered senses, mood changes, impaired body movement, cognitive impairment, or any combination thereof.
  • the NAM reduces or eliminates side effects, the NAM does not compete with or minimize the beneficial effects of THC derived by the subject from using the pharmaceutical compositions.
  • “Dehydro” as used herein refers to a bond, such as a bond between two carbon atoms, wherein each carbon has lost at least one hydrogen atom.
  • a “dihydro” carbon-carbon bond meanwhile, has one more hydrogen atom per carbon in the bond and a lower bond order than the same bond in a dehydro state.
  • ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.
  • the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’.
  • the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.
  • a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1 % to about 5%, but also include individual values (e.g., about 1 %, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.
  • the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined.
  • an “effective amount” of a negative allosteric modulator (NAM) refers to an amount that is sufficient to achieve the desired improvement in the property modulated by the formulation component, e.g. achieving the desired level of modulation of CB1 receptor activity and/or modulation of binding of CB1 ligands.
  • NAM negative allosteric modulator
  • the specific level in terms of wt% in a composition required as an effective amount will depend upon a variety of factors including the amount and type of NAM, amount and type of other ligands present, patient age, sex, and body weight, and condition being treated.
  • a composition the perivascular space and adventitia can contain a composition or formulation disposed on its surface, which can then dissolve or be otherwise distributed to the surrounding tissue and cells.
  • parenteral can include subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques. Administration can be continuous or intermittent.
  • a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition.
  • a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.
  • therapeutic agent can refer to any substance, compound, molecule, and the like, which can be biologically active or otherwise can induce a pharmacologic, immunogenic, biologic and/or physiologic effect on a subject to which it is administered to by local and/or systemic action.
  • a therapeutic agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed.
  • a therapeutic agent can be a secondary therapeutic agent, or in other words, the component(s) of a composition to which an additional part and/or other effect of the composition is attributed.
  • the term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like.
  • therapeutic agents are described in well-known literature references such as the Merck Index (14th edition), the Physicians' Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12th edition), and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.
  • the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, an
  • subject can refer to a vertebrate organism, such as a mammal (e.g. human).
  • Subject can also refer to a cell, a population of cells, a tissue, an organ, or an organism, preferably to human and constituents thereof.
  • the terms “treating” and “treatment” can refer generally to obtaining a desired pharmacological and/or physiological effect.
  • the effect can be, but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof, such as pain, substance abuse, and/or cancer
  • the effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease, disorder, or condition.
  • treatment can include any treatment of pain, substance abuse, and/or cancer in a subject, particularly a human and can include any one or more of the following: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease and/or its symptoms or conditions.
  • treatment as used herein can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment.
  • Those in need of treatment can include those already with the disorder and/or those in which the disorder is to be prevented.
  • the term "treating”, can include inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition.
  • T reating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.
  • dose can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound and/or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration.
  • terapéutica can refer to treating, healing, and/or ameliorating a disease, disorder, condition, or side effect, or to decreasing in the rate of advancement of a disease, disorder, condition, or side effect.
  • an effective amount can refer to the amount of a disclosed compound or pharmaceutical composition provided herein that is sufficient to effect beneficial or desired biological, emotional, medical, or clinical response of a cell, tissue, system, animal, or human.
  • An effective amount can be administered in one or more administrations, applications, or dosages.
  • the term can also include within its scope amounts effective to enhance or restore to substantially normal physiological function.
  • the term “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors within the knowledge and expertise of the health practitioner and which may be well known in the medical arts.
  • the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • the dosage can be adjusted by the individual physician in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the invention (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.
  • prevent refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.
  • prodrug represents those prodrugs of the compounds of the present disclosure which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • Prodrugs of the present disclosure can be rapidly transformed upon in vivo administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a parent compound of the present invention having a structure of a disclosed compound, for example, by hydrolysis in blood.
  • a thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the ACS Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).
  • the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds.
  • exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.
  • the disclosed compounds can possess at least one center of asymmetry, they can be present in the form of their racemates, in the form of the pure enantiomers and/or diastereomers or in the form of mixtures of these enantiomers and/or diastereomers.
  • the stereoisomers can be present in the mixtures in any arbitrary proportions.
  • the disclosed compounds can be present in the form of the tautomers.
  • Acids that can be used to prepare the pharmaceutically acceptable acid-addition salts of the base compounds are those which can form non-toxic acid-addition salts, i.e., salts containing pharmacologically acceptable anions formed from their corresponding inorganic and organic acids.
  • non-toxic acid-addition salts i.e., salts containing pharmacologically acceptable anions formed from their corresponding inorganic and organic acids.
  • inorganic acids include hydrochloric hydrobromic, sulfuric, nitric, phosphoric and the like.
  • organic acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, isethionic, lactic, maleic, malic, mandelicmethanesulfonic, mucic, pamoic, pantothenic, succinic, tartaric, p-toluenesulfonic acid and the like.
  • the acid-addition salt comprises an anion formed from hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion.
  • the compounds of the present disclosure, and/or pharmaceutically acceptable salt(s) thereof can also be administered by controlled release means and/or delivery devices.
  • the compositions can be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
  • temperatures referred to herein are based on atmospheric pressure (i.e. one atmosphere).
  • CBD was obtained by isolating from Cannabis, fiber type, and its purity (>98%) was established using GC/MS and HPLC.
  • the NMR spectra were recorded on Bruker model AMX NMR spectrometers at 400 or 500 MHz ( 1 H) using deuterated solvents CDCh or DMSO-d 6 . Chemical shifts were referenced to the solvent peaks for CHCI3 at 6 H 7.26.
  • the high-resolution mass spectrum (negative mode) was obtained on a JEOL AccuTOF DART 4G, a high-resolution atmospheric pressure ionization, time-of-flight mass spectrometer (HRAPITOFMS) coupled with direct analysis in real-time (DART).
  • Pentafluorobenzeneboronic (PFBA) acid was added to a vigorously stirred ice-cold solution of (1S,4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-enol and 5-heptyl resorcinol in a mixture of dichloromethane and hexafluoroisopropanol and stirred at the same temperature for 24 h.
  • the cooling bath was removed, and the solvent was evaporated to dryness using a rotary evaporator. The residue was adsorbed on celite and purified by flash column chromatography using 2-7% ethyl acetate in hexanes to get the desired compound in 61% yield.
  • CP55.940 (Cat. No. # 13608), was purchased from Cayman Chemical (Ann Arbor, Michigan 48108 USA) and stored at -20 °C. H4-CBD and CBDP were provided by investigators at the University of Mississippi to investigators at the University of Saskatchewan. Investigators at the University of Saskatchewan received coded compounds were blinded to compound identity. Unless specifically noted, all other materials (ethanol, DMSO, and phosphate-buffered saline, etc.) were from Sigma-Aldrich (Mississauga, ON). DMSO was added directly to the media at the indicated concentrations and times indicated, with a final concentration of 0.1% in assay media to dissolve the compounds. DMSO 0.1% was used as the vehicle control for all experiments.
  • CHO-K1 cells expressing human CB1 were used in this experiment.
  • the cells were maintained at 37 °C and 5% CO2 in F-12 DMEM containing 1 mM L- glutamine, 1 % penicillin-streptomycin, hygromycin B (300 pg/mL), and G418 (600 pg/mL) and 10% FBS.
  • CHO-K1 hCB1 cells were used to determine the inhibition of forskolin (FSK)-stimulated cAMP.
  • Low-volume 384-well plates containing Opti-MEM containing 1% FBS at 37 °C and 5% CO2 incubated overnight were used to cultivate 5,000 CHO-K1 hCB1 cells/well.
  • Opti-MEM was discarded and replaced by the cell assay buffer (DiscoveRx).
  • the cells were simultaneously treated with the compounds and 10 pM FSK for 90 min at 37 °C.
  • cAMP antibody and working detection solutions were added according to the manufacturer’s directions (DiscoveRx), and an additional 60-min incubation was done at room temperature.
  • the DiscoveRx cAMP solution A was added, and further incubation was done for 60 minutes at room temperature.
  • chemiluminescence was measured on a Cytation5 plate reader (top read, gain 200, integration time 10,000 ms).
  • Diluted Lipofectamine 3000 reagent was then added to the diluted plasmid solution, and the resultant solution was incubated for 15 min at room temperature. Following this, the Lipofectamine plasmid solution was added to the cells and cells were incubated for 48 h at 37 °C under 5% CO 2 prior to membrane collection (described below). Cells were transfected with 0.50 pg plasmid per plate. Radioligand binding assays were performed as described in previous work. Assays used 1 nM [ 3 H]-SR141716A and Tris binding buffer (50 mM Tris-HCI, 50 mM Tris-base, 0.1% BSA, pH 7.4), in a total assay volume of 500 pL.
  • Binding was initiated by the addition of transfected /?CB1 CHO cell membranes (25 pg protein per well). All assays were performed at 37°C for 120 min prior to guenching with ice-cold Tris binding buffer followed by vacuum filtration using a 12-well sampling manifold (Brandel, Inc., Gaithersburg, MD, USA) and Brandel GF/B filters. Each reaction well was washed three times with 1 mL aliquots of T ris-binding buffer. The filters were air-dried overnight and then placed in 5 mL of scintillation fluid (Ultima Gold XR, Perkin Elmer, Inc., Waltham, MA, USA). Liquid scintillation spectrometry was used for quantifying radioactivity.
  • H4-CBD and CBDP were synthesized as described above and diluted to a range of concentrations in a vehicle composed of ethyl alcohol, cremophor, and sterile saline in the ratio 1 :1 :8, volume/volume.
  • mice were housed in five groups with a 12 h light/12 h dark cycle, and food and water were provided ad libitum. Treatment groups were randomized. Procedures involving animals were performed according to the guidelines approved by the Institutional Animal Care and Use Committee of the University of Mississippi and according to the National Institutes of Health Guide for Care and Use of Laboratory Animals [Application No.: 22-003],
  • mice Thirty minutes prior to baseline testing, mice were acclimated to the testing room. Preinjection baseline catalepsy bar, hot plate, tail-flick latency times, and core body temperature were recorded. Mice were injected intraperitoneally (i.p.) with the test compound, followed by THC injection at a 15-minute interval.
  • mice were individually placed in activity chambers (San Diego Instruments, CA, USA), where the animals underwent a 15-minute acclimation period followed by a 30-minute testing period for locomotor activity. Total activity was expressed as the number of horizontal beam breaks during the 30-minute testing period. Each mouse then had its forepaws placed on a raised bar (4 cm in height), and their latency to either withdraw forepaws from the bar or climb onto the bar was recorded to the nearest second. Mice were removed from the bar after 30 seconds if no response was observed.
  • mice were acclimated to the testing room.
  • each mouse was placed in an open field with two identical objects (Stoelting, IL, USA) approximately five centimeters apart. Mice were given ten minutes to explore the objects. Mice were returned to the home cage and given a 4-hour inter-trial interval (ITI). After the four hours (ITI), one of the identical objects was replaced with a novel object, and mice were given ten minutes to explore the objects. The length of time exploring each object in both the training and testing phases was recorded.
  • CHO cells stably-expressing CB1 were treated with 0.1 nM - 10 pM CP55,940, H4-CBD, or CBDP; or CP55.940 and 1 nM, 100 nM, or 10 pM of H4-CBD or CBDP and the inhibition of forskolin-stimulated cAMP accumulation was measured in the HitHunter assay (FIGs. 1A-1C) (Table 1). H4-CBD and CBDP produced a small degree of agonism (27% and 32%, respectively) at the highest concentration tested (FIG.
  • H4-CBD and CBDP both produced concentrationdependent decreases in potency (as indicated by the rightward shift of the concentrationresponse curve and decreasing pEC 5 o values) and efficacy (as indicated by the downward shift of the concentration-response curve and decreasing E max values) (FIGs. 1B-1C, Table 1). These observations with H4-CBD and CBDP are consistent with previously published literature and the notion that these compounds behave as CB1 NAMs (FIGs. 1 B-1C).
  • H4-CBD and CBDP displayed moderate affinity for wild-type CB1 (33 nM and 65 nM, respectively) (Table 2); compared to the CB1 agonist CP55.940 (2.1 nM).
  • the reference compound, CBD displayed a much lower affinity (380 nM) than previously reported (FIG. 1D).
  • the tetrad assay is a series of behavioral tests that exemplifies the pharmacological effects of cannabinoids. THC has been shown to produce decreases in spontaneous activity, catalepsy, hypothermia, and antinociception. In the current study, the open field data was collected 15 minutes post-THC administration and run for an additional 15 minutes (a total of 30 min). Data were collected after the 30 minute in the open field, approximately 45 to 55 minutes from post-THC administration, for catalepsy, hot plate, tail-flick, and body temperature measurements.
  • the object recognition test is a commonly used behavioral assay to investigate various aspects of learning and memory in mice.
  • ORT object recognition test
  • the data in the graph was obtained after the subsequent 4-hour consolidation period.
  • All groups showed a significant increase in test performance compared to control training, except the THC/vehicle (green bar) group, as anticipated with the THC-alone group (FIG. 5).
  • the results showed that the combination of H4-CBD and A 9 -THC significantly improved mice's learning capacity and mitigated the cognitive impairment induced by A 9 -THC.
  • a combination of CBDP and A 9 -THC also exerted a main effect of treatment.
  • We did not observe any effect of CBDP alone in increasing the latency to paw withdrawal (FIG. 7A).
  • CBDP cannabidiol
  • H4-CBD cannabidiol
  • CB1 NAM effects were further explored in mitigating the A 9 -THC-induced impairment of cognitive function without altering the beneficial effects of THC considering tetrad effects (antinociception, hypothermia, hypolocomotion, and catalepsy) and novel object recognition test in combination with THC.
  • THC central nervous system

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Abstract

Selon un aspect, la divulgation concerne l'utilisation de modulateurs allostériques négatifs (NAM) du récepteur cannabinoïde 1 (CB1) et des compositions pharmaceutiques les comprenant dans des méthodes de traitement ou de prévention de maladies ou de troubles comprenant l'abus de substances, l'anxiété, la douleur, l'obésité, les cancers, les troubles neurodégénératifs et les troubles du système nerveux central (SNC). Selon un aspect, le NAM peut être choisi parmi H4-CBD ou CBDP. Selon certains aspects, les compositions pharmaceutiques comprennent en outre du Δ9-tétrahydrocannabinol (THC), et les NAM de CB1 réduisent ou éliminent les effets secondaires neurologiques indésirables de THC tout en préservant ses effets d'atténuation de maladie et de symptôme.
PCT/US2025/014952 2024-02-07 2025-02-07 Utilisation de phytocannabinoïdes et de leurs analogues en tant que modulateurs allostériques négatifs du récepteur cb1 Pending WO2025171222A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120172339A1 (en) * 2009-07-10 2012-07-05 Northeastern University Angiogenic resorcinol derivatives
WO2022115921A1 (fr) * 2020-12-04 2022-06-09 Cymra Life Sciences Limited Compositions anti-inflammatoires comprenant du cannabidiol, du delta-9-tétrahydrocannabinol et du linalool
WO2022133544A1 (fr) * 2020-12-23 2022-06-30 Botanix Pharmaceuticals Limited Cannabinoïdes cbd et analogues de cannabinoïdes cbd
WO2022221960A1 (fr) * 2021-04-23 2022-10-27 Medipure Pharmaceuticals Inc. Composés pour le traitement de maladies ou d'états pathologiques induits par les récepteurs activés par les proliférateurs de peroxysomes (ppar)
US20240024253A1 (en) * 2022-07-21 2024-01-25 Pike Therapeutics Inc. Continuous Drug Delivery Systems and Methods
WO2025006693A1 (fr) * 2023-06-30 2025-01-02 University Of Mississippi Composés de type cannabidiol et leurs procédés de préparation sélective

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120172339A1 (en) * 2009-07-10 2012-07-05 Northeastern University Angiogenic resorcinol derivatives
WO2022115921A1 (fr) * 2020-12-04 2022-06-09 Cymra Life Sciences Limited Compositions anti-inflammatoires comprenant du cannabidiol, du delta-9-tétrahydrocannabinol et du linalool
WO2022133544A1 (fr) * 2020-12-23 2022-06-30 Botanix Pharmaceuticals Limited Cannabinoïdes cbd et analogues de cannabinoïdes cbd
WO2022221960A1 (fr) * 2021-04-23 2022-10-27 Medipure Pharmaceuticals Inc. Composés pour le traitement de maladies ou d'états pathologiques induits par les récepteurs activés par les proliférateurs de peroxysomes (ppar)
US20240024253A1 (en) * 2022-07-21 2024-01-25 Pike Therapeutics Inc. Continuous Drug Delivery Systems and Methods
WO2025006693A1 (fr) * 2023-06-30 2025-01-02 University Of Mississippi Composés de type cannabidiol et leurs procédés de préparation sélective

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