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WO2024263563A1 - Modulateurs allostériques positifs du sous-type-2 et -3 du récepteur métabotropique du glutamate et leurs utilisations - Google Patents

Modulateurs allostériques positifs du sous-type-2 et -3 du récepteur métabotropique du glutamate et leurs utilisations Download PDF

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Publication number
WO2024263563A1
WO2024263563A1 PCT/US2024/034470 US2024034470W WO2024263563A1 WO 2024263563 A1 WO2024263563 A1 WO 2024263563A1 US 2024034470 W US2024034470 W US 2024034470W WO 2024263563 A1 WO2024263563 A1 WO 2024263563A1
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Prior art keywords
compound
deuterium
pharmaceutically acceptable
mmol
disorder
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Nicholas David Peter Cosford
Dhanya RAVEENDRA-PANICKAR
Douglas J. Sheffler
John Howard Hutchinson
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Sanford Burnham Prebys Medical Discovery Institute
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Sanford Burnham Prebys Medical Discovery Institute
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/402—1-aryl substituted, e.g. piretanide
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings

Definitions

  • metabotropic glutamate subtype -2 and -3 (mGlu2/3) (collectively Group II mGlus) receptor positive allosteric modulators, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders in which metabotropic glutamate receptors are involved.
  • metabotropic glutamate subtype -2 and -3 (mGlu2/3) (collectively Group II mGlus) receptor positive allosteric modulators, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders in which metabotropic glutamate receptors are involved.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each selected from hydrogen or deuterium, provided that at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is deuterium; and wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 that is deuterium has a deuterium enrichment of at least 90%.
  • R 10 and R 11 is deuterium. In some embodiments, R 10 and R 11 are each deuterium. In some embodiments, at least two of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are deuterium. In some embodiments, at least four of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are deuterium. In some embodiments, R 4 , R 5 , R 6 , and R 7 are each deuterium. In some embodiments, R 2 , R 3 , R 8 , and R 9 are each deuterium.
  • R 1 , R 2 , R 3 , R 8 , and R 9 are each deuterium.
  • the compound of Formula (I) is selected from: or a pharmaceutically acceptable salt thereof.
  • each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 that is deuterium has a deuterium enrichment of at least about 95%.
  • each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 that is deuterium has a deuterium enrichment of at least 98%. In some embodiments, each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 that is deuterium has a deuterium enrichment of no more than 99.9%.
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof, and a pharmaceutically acceptable excipient.
  • ring B is unsubstituted cyclopentyl.
  • ring B is cyclopentyl substituted with -OH.
  • ring B is selected from: .
  • ring B is cyclopentenyl optionally substituted with one or more -OH.
  • ring B is selected from: embodiments, the compound of Formula (II), is selected from:
  • a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration.
  • the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion.
  • a method of treating a central nervous disorder (CNS) disorder in a subject in need thereof comprising a step of administering to the subject in need thereof, a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, thereby treating the disorder.
  • the CNS disorder is a neurodegenerative disease.
  • the CNS disorder is schizophrenia.
  • the neurodegenerative disease is Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, or Lou Gehrig's disease (Amyotrophic Lateral Sclerosis or ALS).
  • a method of treating substance abuse in a subject in need thereof comprising the step of administering to the subject in need thereof, a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is sufficient to diminish, inhibit or eliminate desire for and/or consumption of the substance in the subject.
  • the substance is nicotine, alcohol, an opioid, an amphetamine, a methamphetamine, or cocaine.
  • a method for treating an addictive disorder in a subject in need thereof comprising the steps of: a) administering to the subject in need thereof, an effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, during a first time period wherein the subject expects to be in an environment wherein, or exposed to stimuli in the presence of which, the subject habitually uses an addictive substance; and b) administering an effective amount of the compound of any one of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, during a second time period wherein the subject is suffering from withdrawal.
  • the addictive disorder is nicotine addiction.
  • the addictive disorder is alcohol addiction.
  • the addictive disorder is opioid addiction.
  • the addictive disorder is amphetamine addiction.
  • the addictive disorder is methamphetamine addiction.
  • the addictive disorder is cocaine addiction.
  • Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS), mediating fast synaptic transmission through ion channels, primarily the a- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMP A) and kainate ionotropic glutamate receptor subtypes.
  • the metabotropic glutamate (mGlu) receptors are a family of eight G protein-coupled receptors that are activated by glutamate and perform a modulatory function in the nervous system.
  • the Group II mGlu receptors include the mGlu2 and mGlu3 receptor subtypes, which couple with Gi/o proteins to negatively regulate the activity of adenylyl cyclase.
  • mGlu2 receptors act predominantly as presynaptic autoreceptors to modulate the release of glutamate into the synaptic cleft (Cartmell, J. and Schoepp, D. D. J. Neurochem. 2000, 75, 889-907).
  • mGlu3 receptors exhibit a broad distribution in the brain and have been shown to be present on astrocytes (Durand, D. et al. Neuropharmacology 2013, 66, 1-11).
  • mGlu2 and mGlu3 receptor binding display high levels of mGlu2 and mGlu3 receptor binding.
  • This distribution pattern suggests a role for the mGlu2/3 receptor subtypes in the pathology of neuropsychiatric disorders such as anxiety, depression, schizophrenia, drug dependence, neuroprotection, Alzheimer’s disease, and sleep/wake architecture.
  • neuropsychiatric disorders such as anxiety, depression, schizophrenia, drug dependence, neuroprotection, Alzheimer’s disease, and sleep/wake architecture.
  • PAMs positive allosteric modulators
  • a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range.
  • description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • assessing refers to a form of measurement.
  • the term includes determining if an element is present or not (for example, detection). This term can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute depending on the context.
  • a “subject” can be a biological entity containing expressed genetic materials.
  • the biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa.
  • the subject can be tissues, cells and their progeny of a biological entity obtained in vivo or cultured in vitro.
  • the subject can be a mammal.
  • the mammal can be a human.
  • the subject may be diagnosed or suspected of being at high risk for a disease. In some cases, the subject is not necessarily diagnosed or suspected of being at high risk for the disease.
  • zzz vivo is used to describe an event that takes place in a subject’s body.
  • ex vivo is used to describe an event that takes place outside of a subject’s body.
  • An ex vivo assay is not performed on a subject. Rather, it is performed upon a sample separate from a subject.
  • An example of an ex vivo assay performed on a sample is an “zzz vitro" assay.
  • zzz vitro is used to describe an event that takes places contained in a container for holding laboratory reagent such that it is separated from the biological source from which the material is obtained.
  • In vitro assays can encompass cell-based assays in which living or dead cells are employed.
  • In vitro assays can also encompass a cell-free assay in which no intact cells are employed.
  • the term “about” a number refers to that number plus or minus 10% of that number.
  • the term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.
  • treatment or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient.
  • beneficial or desired results include but are not limited to a therapeutic benefit and/or a prophylactic benefit.
  • a therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated.
  • a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • a prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.
  • the terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • the terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which may relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each selected from hydrogen or deuterium, provided that at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is deuterium; and wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 that is deuterium has a deuterium enrichment of at least 90%.
  • R 10 and R 11 are deuterium.
  • R 10 is deuterium.
  • R 10 has a deuterium enrichment of at least 90 % percent.
  • R 10 has a deuterium enrichment of at least 95 % percent.
  • R 10 has a deuterium enrichment of at least 98 % percent.
  • R 10 has a deuterium enrichment of at least 99 % percent.
  • R 10 has a deuterium enrichment of at least 99.5 % percent.
  • R 10 has a deuterium enrichment of at least 99.9 % percent.
  • R 10 and R 11 are each deuterium.
  • R 10 and R 11 each have a deuterium enrichment of at least 90 %. In some embodiments, R 10 and R 11 each have a deuterium enrichment of at least 95 %. In some embodiments, R 10 and R 11 each have a deuterium enrichment of at least 98 %. In some embodiments, R 10 and R 11 each have a deuterium enrichment of at least 99 %. In some embodiments, R 10 and R 11 each have a deuterium enrichment of at least 99.5 %. In some embodiments, R 10 and R 11 each have a deuterium enrichment of at least 99.9 %.
  • At least two of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are deuterium. In some embodiments, at least two of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 have a deuterium enrichment of at least 80 %. In some embodiments, at least two of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 have a deuterium enrichment of at least 90 %.
  • At least two of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 have a deuterium enrichment of at least 95 %. In some embodiments, at least two of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 have a deuterium enrichment of at least 98 % enriched with deuterium. In some embodiments, at least two of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 have a deuterium enrichment of at least 99 %.
  • At least four of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are deuterium. In some embodiments, at least four of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 have a deuterium enrichment of at least 80 percent. In some embodiments, at least four of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 have a deuterium enrichment of at least 90 percent.
  • At least four of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 have a deuterium enrichment of at least 95 percent. In some embodiments, at least four of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 have a deuterium enrichment of at least 98 percent. In some embodiments, at least four of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 have a deuterium enrichment of at least 99 percent.
  • R 4 , R 5 , R 6 , and R 7 are each deuterium. In some embodiments, R 4 , R 5 , R 6 , and R 7 each have a deuterium enrichment of at least 80 percent. In some embodiments, R 4 , R 5 , R 6 , and R 7 each have a deuterium enrichment of at least 90 percent. In some embodiments, R 4 , R 5 , R 6 , and R 7 each have a deuterium enrichment of at least 95 percent. In some embodiments, R 4 , R 5 , R 6 , and R 7 each have a deuterium enrichment of at least 98 percent.
  • R 4 , R 5 , R 6 , and R 7 each have a deuterium enrichment of at least 99 percent.
  • R 2 , R 3 , R 8 , and R 9 are each deuterium.
  • R 2 , R 3 , R 8 , and R 9 each have a deuterium enrichment of at least 80 percent.
  • R 2 , R 3 , R 8 , and R 9 each have a deuterium enrichment of at least 90 percent.
  • R 2 , R 3 , R 8 , and R 9 each have a deuterium enrichment of at least 95 percent.
  • R 2 , R 3 , R 8 , and R 9 each have a deuterium enrichment of at least 98 percent. In some embodiments, R 2 , R 3 , R 8 , and R 9 each have a deuterium enrichment of at least 99 percent. In some embodiments, R 1 , R 2 , R 3 , R 8 , and R 9 are each deuterium. In some embodiments, R 1 , R 2 , R 3 , R 8 , and R 9 each have a deuterium enrichment of at least 80 percent. In some embodiments, R 1 , R 2 , R 3 , R 8 , and R 9 each have a deuterium enrichment of at least 90 percent.
  • R 1 , R 2 , R 3 , R 8 , and R 9 each have a deuterium enrichment of at least 95 percent. In some embodiments, R 1 , R 2 , R 3 , R 8 , and R 9 each have a deuterium enrichment of at least 98 percent. In some embodiments, R 1 , R 2 , R 3 , R 8 , and R 9 each have a deuterium enrichment of at least 99 percent.
  • the compound of Formula (I) is selected from: embodiments, each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 that is deuterium has a deuterium enrichment of at least about 95%. In some embodiments, each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 that is deuterium has a deuterium enrichment of at least 98%.
  • each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 that is deuterium has a deuterium enrichment of no more than 99.9%.
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • ring B is unsubstituted cyclopentyl.
  • ring B is cyclopentyl substituted with -OH.
  • ring B is
  • ring some embodiments ring B is In some embodiments ring B is . In some embodiments ring B is cyclopentyl substituted with more than one -
  • ring B is selected from:
  • ring B is . In some embodiments ring B is In some embodiments ring B is In some embodiments ring B is In some embodiments ring B is In some embodiments W is selected from: hydrogen embodiments W is selected from: some embodiments, W is hydrogen.
  • a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration.
  • the pharmaceutical composition is formulated for administration to a mammal by intravenous administration.
  • the pharmaceutical composition is formulated for administration to a mammal by subcutaneous administration.
  • the pharmaceutical composition is formulated for administration to a mammal by oral administration.
  • the pharmaceutical composition is formulated for administration to a mammal by inhalation administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by nasal administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by dermal administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by ophthalmic administration.
  • the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion.
  • the pharmaceutical composition is in the form of a tablet.
  • the pharmaceutical composition is in the form of a pill.
  • the pharmaceutical composition is in the form of a capsule.
  • the pharmaceutical composition is in the form of a liquid.
  • the pharmaceutical composition is in the form of a suspension.
  • the pharmaceutical composition is in the form of a gel.
  • the pharmaceutical composition is in the form of a solution.
  • the pharmaceutical composition is in the form of a solvate. In some embodiments, the pharmaceutical composition is in the form of a dispersion. In some embodiments, the pharmaceutical composition is in the form of an ointment. In some embodiments, the pharmaceutical composition is in the form of an emulsion. In some embodiments, the pharmaceutical composition is in the form of a lotion.
  • the compound is any one of the compounds represented in Table 1, or a pharmaceutically acceptable salt or solvate thereof.
  • Table 1
  • a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration.
  • the pharmaceutical composition is formulated for administration to a mammal by intravenous administration.
  • the pharmaceutical composition is formulated for administration to a mammal by subcutaneous administration.
  • the pharmaceutical composition is formulated for administration to a mammal by oral administration.
  • the pharmaceutical composition is formulated for administration to a mammal by inhalation administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by nasal administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by dermal administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by ophthalmic administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet.
  • the pharmaceutical composition is in the form of a pill. In some embodiments, the pharmaceutical composition is in the form of a capsule. In some embodiments, the pharmaceutical composition is in the form of a liquid. In some embodiments, the pharmaceutical composition is in the form of a suspension. In some embodiments, the pharmaceutical composition is in the form of a gel. In some embodiments, the pharmaceutical composition is in the form of a dispersion. In some embodiments, the pharmaceutical composition is in the form of a solution. In some embodiments, the pharmaceutical composition is in the form of a solvate. In some embodiments, the pharmaceutical composition is in the form of an emulsion. In some embodiments, the pharmaceutical composition is in the form of an ointment. In some embodiments, the pharmaceutical composition is in the form of a lotion.
  • a method of treating a central nervous disorder (CNS) disorder in a subject in need thereof comprising a step of administering to the subject in need thereof, a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, thereby treating the disorder.
  • the method of treating a central nervous disorder (CNS) disorder in a subject in need thereof comprises a step of administering to the subject in need thereof, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, thereby treating the disorder.
  • the method of treating a central nervous disorder (CNS) disorder in a subject in need thereof comprises a step of administering to the subject in need thereof, a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, thereby treating the disorder.
  • the method of treating a central nervous disorder (CNS) disorder in a subject in need thereof comprises a step of administering to the subject in need thereof, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, thereby treating the disorder.
  • the method of treating a central nervous disorder (CNS) disorder in a subject in need thereof comprises a step of administering to the subject in need thereof, a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, thereby treating the disorder.
  • the compound of Formula (I) is selected from: embodiments, the compound of Formula (II), is selected from: pharmaceutically acceptable salt thereof.
  • the CNS disorder is an addictive disorder.
  • the addictive disorder is nicotine addiction, alcohol addiction, opioid addiction, amphetamine addiction, methamphetamine addiction, or cocaine addiction.
  • the addictive disorder is nicotine addiction.
  • the addictive disorder is alcohol addiction.
  • the addictive disorder is opioid addiction. In some embodiments, the addictive disorder is opioid addiction. In some embodiments, the addictive disorder is amphetamine addiction. In some embodiments, the addictive disorder is methamphetamine addiction. In some embodiments, the addictive disorder is cocaine addiction. In some embodiments, the CNS disorder is schizophrenia. In some embodiments, the CNS disorder is a neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, or Lou Gehrig's disease (Amyotrophic Lateral Sclerosis or ALS). In some embodiments, the neurodegenerative disease progresses gradually. In some embodiments, the neurodegenerative disease progresses over at least one year.
  • the neurodegenerative disease progresses rapidly. In some embodiments, the neurodegenerative disease progresses in less than one year. In some embodiments, the neurodegenerative disease is hereditary. In some embodiments, the neurodegenerative disease is of environmental origin such as heavy metal exposure.
  • a method of treating substance abuse in a subject in need thereof comprising the step of administering to the subject in need thereof, a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is sufficient to diminish, inhibit or eliminate desire for and/or consumption of the substance in the subject.
  • a method of treating substance abuse in a subject in need thereof comprising the step of administering to the subject in need thereof, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is sufficient to diminish, inhibit or eliminate desire for and/or consumption of the substance in the subject.
  • a method of treating substance abuse in a subject in need thereof comprising the step of administering to the subject in need thereof, a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is sufficient to diminish, inhibit or eliminate desire for and/or consumption of the substance in the subject.
  • the compound of Formula (I) is selected from: embodiments, the compound of Formula (II), is selected from: , or a pharmaceutically acceptable salt thereof.
  • the substance is nicotine, alcohol, opioids, amphetamines, methamphetamines, or cocaine.
  • the substance is nicotine.
  • the substance is alcohol.
  • the substance is an opioid.
  • the substance is one or more opioids.
  • the substance is an amphetamine.
  • the substance is one or more amphetamines.
  • the substance is a methamphetamine.
  • the substance is one or more methamphetamines.
  • the substance is cocaine.
  • a method for treating an addictive disorder in a subject in need thereof comprising the steps of: a) administering to the subject in need thereof, an effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, during a first time period, wherein the subject expects to be in an environment wherein, or exposed to stimuli in the presence of which, the subject habitually uses an addictive substance; and b) administering an effective amount of the compound of any one of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, during a second time period wherein the subject is suffering from withdrawal.
  • the method comprises administering to the subject in need thereof, an effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, during a first time period, wherein the subject expects to be in an environment wherein, or exposed to stimuli in the presence of which, the subject habitually uses an addictive substance.
  • the method comprises administering an effective amount of the compound of any one of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, during a second time period wherein the subject is suffering from withdrawal.
  • the compound of Formula (I) is selected from: , or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (II) is selected from:
  • a method for treating an addictive disorder in a subject in need thereof comprising the steps of: a) administering to the subject an effective amount of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, during a first time period wherein the subject expects to be in an environment in which the subject habitually uses an addictive substance, or exposed to stimuli which results in the subject habitually using an addictive substance; and b) administering to the subject an effective amount of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, during a second time period wherein the subject is suffering from withdrawal.
  • the addictive disorder is nicotine addiction, alcohol addiction, opioid addiction, amphetamine addiction, methamphetamine addiction, or cocaine addiction.
  • the addictive disorder is nicotine addiction.
  • the addictive disorder is alcohol addiction.
  • the addictive disorder is opioid addiction.
  • the addictive disorder is amphetamine addiction.
  • the addictive disorder is methamphetamine addiction.
  • the addictive disorder is cocaine addiction.
  • the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • the compounds described herein exist in their isotopically- labeled forms.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H (D), 3 H, 13 C, 14 C, 15 N, 18 O, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • Compounds described herein, and the pharmaceutically acceptable salts or solvates thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • the natural ratio of about 1 deuterium atom for every 6,600 proton atoms, or about 0.015% may be enriched to a substantially different ratio.
  • Deuterium enrichment factor refers to the increase in ratio of deuterium atoms to hydrogen atoms within a given molecular substituent or position.
  • one or more molecular substituents comprising hydrogen atoms are replaced with one or more molecular substituents comprising deuterium atoms.
  • a position designated as having deuterium has a minimum deuterium enrichment factor of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium position.
  • Deuterium enrichment and deuterium enrichment factor may be confirmed through experimental techniques including nuclear magnetic resonance and mass spectroscopy.
  • a particular atomic position is designated as having deuterium or “D” or “d”, it is understood that the position is enriched with deuterium atoms at that position and is substantially greater than the naturally occurring percentage of deuterium atoms to hydrogen atoms.
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, bromide, chloride, formate, iodide, phosphate, and sulfonate.
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, trifluoroacetic acid, and muconic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like
  • organic acids such as acetic acid, propionic acid, hexanoic acid, trifluoroacetic acid, and muconic acid.
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, or sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, and aluminum salts.
  • bases include sodium hydroxide, potassium hydroxide, and sodium carbonate.
  • Representative organic amines useful for the formation of base addition salts include diisopropylethylamine, piperazine and the like.
  • the compounds described herein exist as solvates.
  • the invention provides for methods of treating diseases by administering such solvates.
  • the invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers may exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • Addiction refers to the repeated desire to consume a substance, composition, or mixture.
  • addiction is towards a substance of abuse.
  • addiction yields adverse effects upon cessation of consuming a substance, composition, or mixture towards which there is an addiction.
  • Withdrawal refers to physiological and psychological effects due to ceasing consumption of an addictive substance or substance of abuse. Withdrawal and its unpleasant effects often complicate the cessation of consuming addictive substances that are toxic or dangerous.
  • Addiction may emerge with respect to a variety of chemical substances and mixtures.
  • addiction is towards a narcotic.
  • substances of addiction are nicotine, alcohol, opioids, amphetamines, methamphetamines, or cocaine.
  • the addiction is towards a certain class of substances such as narcotics, benzodiazepines, serotonin reuptake inhibitors, or norepinephrine reuptake inhibitors.
  • Addictive substances may predominately be a single molecular entity, or a mixture of one or more addictive substances and fillers or excipients.
  • an addictive substance is a single compound in a particular form such as a salt, a suspension, or a dry powder.
  • an addictive substance is one or more compounds. Further physiological and technical aspects of addiction, addictive disorders, withdrawal, and addictive substances may be found in The Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5; American Psychiatric Association, 2013).
  • Anxiety is an unpleasant state of inner turmoil, often accompanied by nervous behavior, such as pacing back and forth, somatic complaints and rumination. It is the subjectively unpleasant feelings of dread over anticipated events, such as the feeling of imminent death. Anxiety is a feeling of fear, worry, and uneasiness, usually generalized and unfocused as an overreaction to a situation that is only subjectively seen as menacing. It is often accompanied by muscular tension, restlessness, fatigue and problems in concentration. Anxiety can be appropriate, but when experienced regularly the individual may suffer from an anxiety disorder.
  • the compounds described herein are mGlu2/3 receptor PAM used for treating anxiety symptoms.
  • the method includes administering to a subject in need thereof, an effective amount of at least one mGlu2/3 receptor PAM, thereby treating the anxiety symptoms.
  • Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behavior, feelings and sense of well-being. People with depressed mood can feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable or restless. They may lose interest in activities that were once pleasurable, experience loss of appetite or overeating, have problems concentrating, remembering details or making decisions, and may contemplate, attempt or commit suicide. Insomnia, excessive sleeping, fatigue, aches, pains, digestive problems or reduced energy may also be present.
  • Depressed mood is a feature of some psychiatric syndromes such as major depressive disorder, but it may also be a normal reaction to life events such as bereavement, a symptom of some bodily ailments or a side effect of some drugs and medical treatments.
  • Blockade of mGlu2/3 receptors has antidepressant properties as reflected in reversal of the negative affective (depression-like) aspects of nicotine withdrawal.
  • blockade of mGlu2 and mGlu3 reverses depression-like symptoms observed during drug withdrawal, and possibly depression observed during drug dependence (Ahmed, S. H., et al. Nature Neuroscience, 5: 625-626 (2002)). Therefore, administration of an effective amount of an antagonist of mGlu2 and mGlu3 is likely to be efficacious for treating non-drug-induced depressions, based on the known neurobiological similarities mediating drug- and non-drug- induced depressions (Markou et al.
  • the compounds described herein are mGlu2/3 receptor PAM used for treating depressive symptoms and anxiety symptoms of depression.
  • the method includes administering to a subject in need thereof, an effective amount of at least one antagonist which modulates the mGlu2 and/or mGlu3 receptor, thereby treating the depressive symptoms and anxiety symptoms.
  • the disclosure provides at least one mGlu2/3 receptor PAM that can be administered during a depressed time period, wherein the subject experiences symptoms of depression.
  • Nicotine dependence is an addiction to tobacco products caused by the drug nicotine. Nicotine dependence means a person can't stop using the substance, even though it's causing harm. Nicotine produces physical and mood-altering effects in your brain that are temporarily pleasing. These effects make you want to use tobacco and lead to dependence. At the same time, stopping tobacco use causes withdrawal symptoms, including irritability and anxiety.
  • the effective amount of at least one mGlu2/3 receptor PAM is administered to decrease nicotine consumption.
  • an effective amount of a PAM of mGlu2 and/or mGlu3 can be administered to decrease nicotine consumption.
  • a PAM of mGlu2 and/or mGlu3 is administered while a subject is experiencing withdrawal.
  • a PAM of mGlu2 and/or mGlu3 is administered during a time period when a subject is actively using an addictive substance.
  • a PAM of mGlu2 and/or mGlu3 is administered during a time period when a subject is actively experiencing depression associated with drug use or not associated with drug use.
  • Cocaine addiction remains a major public health problem in the United States.
  • Conditioned stimuli previously associated with cocaine administration may also elicit conditioned "cravings" leading to the reinstatement of cocaine-seeking behavior even after a prolonged period of abstinence.
  • Recent studies indicate that the neuronal mechanisms underlying various aspects of drug abuse may differ necessitating the use of different treatments for specific aspects of drug dependence.
  • a safe and effective pharmacological treatment for cocaine dependence has yet to be identified.
  • mGluII receptors Group II metabotropic glutamate receptors
  • the mGluII receptor positive modulators may decrease the reinforcing effects of self-administered cocaine in rats that had extended access to cocaine, a putative model of cocaine dependence while having no effect in rats with limited access to cocaine.
  • Positive mGluII receptor modulators may attenuate discriminatory cue-induced reinstatement of cocaine self-administration.
  • mGluII receptor negative modulators may reverse the reward deficits associated with early cocaine abstinence.
  • Cocaine addiction is a chronic relapsing disorder and remains a major public health problem in the United States.
  • the number of cases of cocaine abuse has steadily risen in the past decade.
  • a safe and effective pharmacological treatment for cocaine dependence has yet to be identified, which highlights the need to design new chemical entities that may become future novel medications for cocaine addiction.
  • mGlus play a significant role in the abuse-related effects of cocaine.
  • repeated administration of cocaine has been shown to alter the function of mGlus, as well as their regulation by cysteine/glutamate exchange in the nucleus accumbens.
  • the intravenous drug self-admini strati on procedure provides a reliable and robust model of human drug consumption.
  • This procedure in animals provides a valid model of human drug abuse as studied in a controlled laboratory situation.
  • Self-administration of drugs of abuse is thought to provide an operational measure of the rewarding effects of the drug.
  • Increases in excitatory glutamatergic transmission are likely to contribute to the positive reinforcing properties of addictive drugs.
  • Neurochemical studies indicate that systemic cocaine administration increase glutamate levels in the ventral tegmental area (VTA) and the nucleus accumbens, brain structures that are integral components of the extended amygdala, a brain circuit mediating the reward effects of all major drugs of abuse.
  • VTA ventral tegmental area
  • a positive modulator of mGluII receptors may decrease cocaine self-administration in rats with extended access to cocaine by decreasing glutamate neurotransmission in limbic structures similar to the effects of mGlu2/3 agonists.
  • a negative modulator of mGluII receptors may most likely have no effect on cocaine self-administration, or possibly may shift the dose-response curve to the left, potentiating the reinforcing effects of cocaine.
  • Another challenge for the treatment of drug addiction is chronic vulnerability to relapse.
  • One of the factors that precipitates drug craving and relapse to drug taking behavior in humans is environmental stimuli previously associated with drug-taking.
  • These drug- associated stimuli can be divided into two categories: discrete drug cues (e.g., drug paraphernalia) that are associated with the rewarding effects of the drug, and discriminatory and contextual drug cues (e.g., specific environmental stimuli or specific environments) that predicts drug availability.
  • discrete, discriminative and contextual conditioned cues can reinstate drug-seeking behavior, measured by variables derived from the reinstatement procedure.
  • mGlu2/3 agonists have been shown to inhibit cue-induced reinstatement of heroin-seeking, alcohol-seeking, nicotine-seeking, and also inhibited food-seeking behavior.
  • the decreases in cue-induced food responding suggest that the administration of mGlu2/3 agonist decreased motivation for a natural reinforcer also.
  • susceptibility to relapse due to cue reactivity increases gradually over periods of weeks or months.
  • the administration of a positive modulator of mGluII receptors during prolonged abstinence from cocaine selfadministration may decrease, while a negative modulator of mGluII receptors may have no effect on cocaine-seeking behavior induced by discriminative stimuli associated with cocaine availability.
  • Avoidance and alleviation of the negative affective state of early drug withdrawal with further drug abuse is hypothesized to be an important source of motivation that contributes significantly to the development of compulsive drug use and relapse during early abstinence. It has been hypothesized that susceptibility to relapse due to affective withdrawal symptoms peaks within days of cessation reflecting early rise in withdrawal symptoms. Thus, pharmacological treatments that reverse the depression-like aspects of early cocaine withdrawal would remove an important source of motivation that contributes to relapse to drug abuse shortly after the initial cessation of drug administration. Abrupt abstinence following chronic exposure to drugs of abuse, including cocaine results in a negative affective state reflected in significant elevations in intracranial self-stimulation (ICSS) thresholds.
  • ICSS intracranial self-stimulation
  • ICSS thresholds are thought to provide an operational measure of brain reward function; thus elevations in ICSS thresholds reflect deficits in brain reward function. This threshold elevation is opposite to the lowering of ICSS thresholds observed after cocaine administration that reflects an increase in brain reward function that most likely underlies, or at least relates to, cocaine's euphorigenic effects. This increase in brain reward function associated with cocaine consumption is considered essential for the establishment and maintenance of cocaine self-administration behavior.
  • the mechanisms that contribute to withdrawal-induced reward deficits or reward facilitation remain unclear.
  • Group II mGlus have been implicated in the synaptic adaptations that occur in response to chronic drug exposure and contribute to the aversive behavioral withdrawal syndrome. The role of glutamate transmission in the early phase of cocaine withdrawal has not been studied extensively.
  • the compounds described herein are mGlu2/3 receptor PAM used for treating cocaine addiction.
  • Schizophrenia is a devastating psychiatric illness that afflicts approximately 1% of the worldwide population.
  • the core symptoms observed in schizophrenic patients include positive symptoms (thought disorder, delusions, hallucinations, paranoia), negative symptoms (social withdrawal, anhedonia, apathy, paucity of speech) and cognitive impairments such as deficits in perception, attention, learning, short- and long-term memory and executive function.
  • the cognitive deficits in schizophrenia are one of the major disabilities associated with the illness and are considered a reliable predictor of long-term disability and treatment outcome.
  • Currently available antipsychotics effectively treat the positive symptoms, but provide modest effects on the negative symptoms and cognitive impairments.
  • NMDA receptors involved in these symptoms might reside at glutamatergic synapses on GABAergic projection neurons in midbrain regions as well as GABAergic interneurons and glutamatergic projection neurons in key cortical and limbic regions
  • NMD A receptors localized on GABAergic projection neurons in subcortical regions such as the nucleus accumbens, provides inhibitory control on excitatory glutamatergic thalamocortical neurons that project to pyramidal neurons in the prefrontal cortex (PFC).
  • NMDA receptor function such as activation of metabotropic glutamate receptor subtype 5 (mGlu5) located on GABAergic neurons
  • An alternative approach might be to reduce excitatory glutamatergic transmission at key synapses, such as thalamocortical synapses in the PFC, by activation of metabotropic glutamate receptor subtypes 2 and 3 (mGlu2 and mGlu3) presynaptically located in these synapses.
  • mGlu2 and mGlu3 metabotropic glutamate receptor subtypes 2 and 3
  • group II mGlu receptor agonists are mechanistically related to the antipsychotic actions of these compounds, these actions fit well with current models of disruptions in subcortical and cortical circuits that might be involved in the psychotomimetic effects of NMD A receptor antagonists and the range of symptoms observed in schizophrenia patients.
  • orthosteric agonists of these receptors may reach the market for broad clinical use. Long-term administration of group II mGlu receptor agonists induces robust tolerance in at least one rodent model that has been used to predict antipsychotic efficacy.
  • orthosteric agonists also activate both mGlu2 and mGlu3 and do not provide insights into which of these group II mGlu receptor subtypes is most important for clinical efficacy.
  • recent findings demonstrate that the antipsychotic-like effects of mGlu2/3 receptor agonists are absent in mGlu2-knockout, but not mGlu3 -knockout, mice.
  • positive allosteric modulators of mGlu2 might be an alternative approach that could provide greater selectivity and other potential advantages to orthosteric agonists.
  • group II mGlu receptor agonists are useful in the treatment of schizophrenia.
  • selective mGlu2 PAMs represent a novel approach to the treatment of these disorders that is devoid of the adverse effects associated with currently available drugs.
  • the compounds described herein are mGlu2/3 receptor PAM used for treating schizophrenia.
  • the method includes administering to a subject in need thereof, an effective amount of at least one mGlu2/3 receptor PAM, thereby treating schizophrenia.
  • AD Alzheimer's disease
  • AD also known as Alzheimer disease, or just Alzheimer's
  • a chronic neurodegenerative disease that usually starts slowly and gets worse over time.
  • the most common early symptom is difficulty in remembering recent events (short term memory loss).
  • symptoms can include: problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, not managing self-care, and behavioral issues.
  • the speed of progression can vary, the average life expectancy following diagnosis is three to nine years.
  • Various brain regions including the cerebral cortex, hippocampus, striatum, amygdala, frontal cortex and nucleus accumbens, display high levels of mGlu2 and mGlu3 receptor binding. This distribution pattern suggests a role for the mGlu2/3 receptor subtypes in the pathology of neuropsychiatric disorders such as Alzheimer’s disease.
  • the compounds described herein are mGlu2/3 receptor PAM used for treating Alzheimer’s disease.
  • the method includes administering to a subject in need thereof, an effective amount of at least one mGlu2/3 receptor PAM, thereby treating Alzheimer’s disease.
  • Huntington's disease is a neurodegenerative genetic disorder that affects muscle coordination and leads to mental decline and behavioral symptoms. Symptoms of the disease can vary between individuals and affected members of the same family, but usually progress predictably. The earliest symptoms are often subtle problems with mood or cognition. A general lack of coordination and an unsteady gait often follows. As the disease advances, uncoordinated, jerky body movements become more apparent, along with a decline in mental abilities and behavioral symptoms. Physical abilities gradually worsen until coordinated movement becomes difficult. Mental abilities generally decline into dementia. Complications such as pneumonia, heart disease, and physical injury from falls reduce life expectancy to around twenty years from the point at which symptoms begin. Physical symptoms can begin at any age from infancy to old age, but usually begin between 35 and 44 years of age.
  • Excitotoxic injury to striatum by dysfunctional cortical input or aberrant glutamate uptake may contribute to Huntington's disease (HD) pathogenesis.
  • Daily subcutaneous injection with a maximum tolerated dose (MTD) of the mGlu2/3 agonist LY379268 (20mg/kg) beginning at 4 weeks has been found to dramatically improves the phenotype in R6/2 mice (the most commonly used animal model of Huntington’s disease) (Reiner et al. Brain Research 1473 (2012) 161-172). For example, normalization of motor function in distance traveled, speed, the infrequency of pauses, and the ability to locomote in a straight line, and a rescue of a 15-20% striatal neuron loss at 10 weeks were observed.
  • the compounds described herein are mGlu2/3 receptor PAM used for treating Huntington’s disease.
  • the method includes administering to a subject in need thereof, an effective amount of at least one mGlu2/3 receptor PAM, thereby treating Huntington’s disease.
  • ALS Amyotrophic lateral sclerosis
  • Lou Gehrig Lou Gehrig’s Disease
  • Riluzole is the only drug that improves survival of ALS patients, only to a modest extent.
  • Familial ALS FALS
  • SOD1 type-1 superoxide dismutase
  • Enhancement of glial-derived neurotrophic factor is an established therapeutic target for amyotrophic lateral sclerosis (ALS).
  • GDNF group II metabotropic glutamate
  • LY379268 group II metabotropic glutamate
  • LY379268 protected Stemberger monoclonal incorporated antibody-32 (SMI-32)+ motor neurons against excitotoxic death in mixed cultures of spinal cord cells, and its action was abrogated by anti -GDNF antibodies.
  • Acute systemic injection of LY379268 (0.5, 1 or 5 mg/kg, i.p.) enhanced spinal cord GDNF levels in wild-type and mGlu2 knockout mice, but not in mGlu3 knockout mice. No tolerance developed to the GDNF-enhancing effect of LY379268 when the drug was continuously delivered for 28 days by means of s.c. osmotic minipumps (0.5-5 mg/day). Continuous infusion of LY379268 also enhanced the expression of the glutamate transporter GLT-1, in the spinal cord. Continuous treatment with 1 or 5 mg/kg/day with LY379268 had a beneficial effect on neurological disability in SOD1G93A mice.
  • the compounds described herein are mGlu2/3 receptor PAM used for treating ALS.
  • the method includes administering to a subject in need thereof, an effective amount of at least one mGlu2/3 receptor PAM, thereby treating ALS.
  • Parkinson’s disease is a chronic movement disorder resulting from a disturbance in the normal functioning of the basal ganglia, a collection of subcortical nuclei that are essential for the initiation and control of motor activity.
  • the underlying pathology of the disease is a progressive degeneration of the dopaminergic nigrostriatal tract that manifests as a range of motor deficits including akinesia or bradykinesia, tremor, rigidity and postural instability.
  • Current therapies for PD are essentially based on dopamine replacement and include levodapa (L-DOPA), a precursor of dopamine, and dopamine receptor agonists.
  • the compounds described herein are mGlu2/3 receptor PAM used for treating Parkinson’s disease.
  • the method includes administering to a subject in need thereof, an effective amount of at least one mGlu2/3 receptor PAM, thereby treating Parkinson’s disease.
  • GDNF glial cell line-derived neurotrophic factor
  • striatal GDNF levels (0.25 or 3 mg/kg, i.p.) were highly protective against nigro-striatal damage induced by 1- methyl-4- phenyl-l,2,3,6-tetrahydropyridine in mice, as assessed by stereological counting of tyrosine hydroxylase-positive neurons in the pars compacta of the substantia nigra.
  • selective mGlu3 receptor agonists or enhancers are potential candidates as neuroprotective agents in Parkinson’s disease, and their use might circumvent the limitations associated with the administration of exogenous GDNF.
  • a compound of Formula (I) or Formula (II) is coadministered with a second therapeutic agent, wherein the compound of Formula (I) or Formula (II) and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
  • dosages of the co-administered compounds vary depending on the type of co-drug(s) employed, on the specific drug(s) employed, on the disease or condition being treated and so forth.
  • the compound provided herein when co-administered with one or more other therapeutic agents, is administered either simultaneously with the one or more other therapeutic agents, or sequentially.
  • the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms.
  • compounds of Formula (I) or Formula (II) are administered to a mammal in combination with one or more additional neurodegenerative disease or disorder therapeutic agent.
  • the neurodegenerative disease or disorder is Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, or Lou Gehrig's Disease (Amyotrophic Lateral Sclerosis or ALS).
  • compounds of Formula (I) or Formula (II) are administered to a mammal in combination with one or more additional therapeutic agent that alleviate the symptoms or side effects of a neurodegenerative disease or disorder.
  • the symptoms or side effects a neurodegenerative disease or disorder are dementia, memory loss, dyskinesias, cognitive impairment, tremors, rigidity, slowness of movement, postural instability, involuntary jerking or writhing movements (chorea), slow or abnormal eye movements, difficulty with the physical production of speech or swallowing, psychiatric disorders, muscle cramps and spasms, spasticity, constipation, fatigue, excessive salivation, excessive phlegm, pain, depression, sleep problems, uncontrolled outbursts of laughing or crying.
  • the additional therapeutic agent is an Alzheimer’s disease therapeutic agent.
  • the additional therapeutic agent is a cholinesterase inhibitor.
  • the cholinesterase inhibitor is donepezil, galantamine, or rivastigmine.
  • the additional therapeutic agent is memantine.
  • the additional therapeutic agent is latrepirdine, idalopridine, or cerlapirdine.
  • the additional therapeutic agent is a Parkinson’s disease therapeutic agent.
  • the additional therapeutic agent is levodopa.
  • the additional therapeutic agent is carbidopa-levodopa.
  • the additional therapeutic agent is a Dopamine agonist.
  • the dopamine agonist is ropinirole, pramipexole, or rotigotine.
  • the additional therapeutic agent is a MAO-B inhibitor.
  • the MAO-B inhibitor is selegiline or rasagiline.
  • the additional therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor.
  • the COMT inhibitor is entacapone or tolcapone.
  • the additional therapeutic agent is an Anticholinergic.
  • the anticholinergic is benztropine or trihexyphenidyl.
  • the additional therapeutic agent is amantadine. [0099]
  • compounds of Formula (I) or Formula (II) are administered to a mammal in combination with deep brain stimulation.
  • the additional therapeutic agent is a Huntington’s disease therapeutic agent.
  • the additional therapeutic agent is tetrabenazine.
  • the additional therapeutic agent is an antipsychotic drug.
  • the antipsychotic drug is haloperidol, chlorpromazine, risperidone, olanzapine or quetiapine.
  • the additional therapeutic agent is amantadine, levetiracetam, or clonazepam.
  • the additional therapeutic agent is an antidepressant.
  • the antidepressant is citalopram, fluoxetine, or sertraline.
  • the additional therapeutic agent is a mood-stabilizing drug.
  • the mood-stabilizing drug is valproate, carbamazepine, or lamotrigine.
  • compounds of Formula (I) or Formula (II) are administered to a mammal in combination with psychotherapy, speech therapy, physical therapy or occupational therapy.
  • the additional therapeutic agent is a Lou Gehrig's Disease (Amyotrophic Lateral Sclerosis or ALS) therapeutic agent.
  • the additional therapeutic agent is riluzole.
  • the additional therapeutic agent is baclofen, diazepam, trihexyphenidyl or amitriptyline.
  • compounds of Formula (I) or Formula (II) are administered to a mammal in combination with one or more additional neuropsychiatric disease or disorder therapeutic agent.
  • a compound of Formula (I) is administered to a mammal in combination with one or more additional neuropsychiatric disease or disorder therapeutic agent.
  • a compound of Formula (II) is administered to a mammal in combination with one or more additional neuropsychiatric disease or disorder therapeutic agent.
  • the neuropsychiatric disease or disorder is schizophrenia, anxiety, a sleep disorder, eating disorder, psychosis, or addiction.
  • the neuropsychiatric disease or disorder is schizophrenia.
  • the neuropsychiatric disease or disorder is anxiety. In some embodiments, the neuropsychiatric disease or disorder is sleep disorder. In some embodiments, the neuropsychiatric disease or disorder is an eating disorder. In some embodiments, the neuropsychiatric disease or disorder is psychosis. In some embodiments, the neuropsychiatric disease or disorder is schizophrenia. In some embodiments, the neuropsychiatric disease or disorder is an addictive disorder. In some embodiments, the neuropsychiatric disease or disorder is addiction.
  • compounds of Formula (I) or Formula (II) are administered in combination with one or more additional anti-addiction therapeutic agent.
  • compounds of Formula (I) or Formula (II) are administered in combination with one or more additional anti-addiction therapeutic agent for the treatment of a substance use and/or substance abuse disorder.
  • the substance use disorder is a nicotine use disorder, a stimulant use disorder, an alcohol use disorder, or an opioid use disorder.
  • the substance use disorder is a nicotine use disorder.
  • the substance use disorder is a stimulant use disorder.
  • the substance use disorder is an alcohol use disorder.
  • the substance use disorder is an opioid use disorder.
  • the anti-addiction therapeutic agent is selected from the group consisting of buprenorphine, methadone, naltrexone, subozone, naloxone, acamprosate, disulfiram, bupropion, varenicline, and a nicotine replacement therapy (NRT).
  • the additional therapeutic agent is an antipsychotic.
  • the antipsychotic is aripiprazole, asenapine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, chlorpromazine, fluphenazine, haloperidol, or perphenazine.
  • the additional therapeutic agent is an antidepressant.
  • the antidepressant is a selective serotonin reuptake inhibitor (SSRI) or a serotonin norepinephrine reuptake inhibitor (SNRI).
  • the antidepressant is escitalopram, duloxetine, venlafaxine, or paroxetine.
  • the additional therapeutic agent is an anti-anxiety medication.
  • the anti-anxiety medication is buspirone.
  • the additional therapeutic agent is a benzodiazepine.
  • the benzodiazepine is alprazolam, chlordiazepoxide, diazepam, or lorazepam.
  • the additional therapeutic agent is a medication used to treat dependence.
  • the medication used to treat dependence is buprenorphine, methadone, naltrexone, subozone, naloxone, acamprosate, disulfiram, bupropion, varenicline, or a nicotine replacement therapy (NRT).
  • the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fisher Scientific (Fisher Chemicals), and Acros Organics.
  • the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols.
  • Ester (A) (0.4 mmol) was dissolved in tetrahydrofuran (10 mL), 2M Li OH (2 mmol) was added and the mixture was heated at reflux for 30 min. The solvent was evaporated and the residue was dissolved in water and acidified using 2M HC1. The aqueous layer was extracted with EtOAc (3 x 10 mL) and the combined organic layer was washed with water, brine and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo to obtain the crude acid (B) as a yellow solid. The crude residue was purified by reverse phase column chromatography (Acetonitrile; H2O solvent system) to give the desired carboxylic acid (B).
  • Example 1 Synthesis of 4-Chloro-[l,l'-biphenyl]-3,3'-dicarboxylic acid [0124] 5 -Borono-2-chlorobenzoic acid (0.3 g, 1.5 mmol), 3 -bromobenzoic acid (0.2 g, 1 mmol) Pd(dppf)C12 (0.073 g, 0.1 mmol) and 2M Na2COs (2 mL) were taken in DME (10 mL), the resulting mixture was heated at 80 °C for 2 h under an atmosphere of nitrogen, after completion of the reaction, the reaction mixture was cooled to rt, diluted with water and acidified using dil.
  • Step 2 ,
  • the product was extracted with EtOAc (3 x 25 mL) and washed with brine and the organic layer was dried over anhydrous Na2SO4. The solvent was evaporated in vacuum to obtain the crude product.
  • the crude product was purified using automated prep-HPLC to yield the desired compound as a white solid (0.31 g, 67%).
  • LiAlD4 (0.129 g, 3 mmol) was suspended in THF (6 mL) and cooled to 0 °C in an ice bath. A solution of methyl 3 -bromobenzoate (1.07 g, 5 mmol ) in THF (1 mL) was added dropwise via syringe. The reaction slurry was allowed to warm to room temperature overnight and then quenched by the subsequent addition of EtOAc (15 mL) and after 30 min of H2O (3 x 5 mL). The white suspension was filtered and the residue washed with DCM (6 x 50 mL). The filtrate was dried over MgSCh and the solvent was removed under reduced pressure to yield 3-bromophenyl)methan-d2-ol. Colorless viscous liquid (0.89 g, 94%).
  • the aqueous mixture was extracted with EtOAc (3 x 20 mL) and washed with brine and the organic layer was dried over anhydrous Na2SO4. The solvent was evaporated in vacuum to obtain the crude product.
  • the crude product was purified using automated prep-HPLC to yield the desired compound as a white solid (0.218 g, 63%).
  • a parenteral pharmaceutical composition suitable for administration by injection 100 mg of a water-soluble salt of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt or solvate thereof, is dissolved in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL. The mixture is incorporated into a dosage unit form suitable for administration by injection.
  • a pharmaceutical composition for oral delivery 100 mg of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt or solvate thereof, is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit, such as a hard gelatin capsule, which is suitable for oral administration.
  • an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.
  • HEK-293 Human Embryonic Kidney (HEK-293) cell lines co-expressing rat mGlu receptors 2, 3, 4, 6, 7 or 8 and G protein-coupled inwardly-rectifying potassium (GIRK) channels were grown in Growth Media containing 45% DMEM, 45% F-12, 10% FBS, 20 mM HEPES, 2 mM L-glutamine, antibiotic/antimycotic, non-essential amino acids, 700 pg/mL G418, and 0.6 pg/mL puromycin at 37 °C in the presence of 5% CO2.
  • Cells expressing rat mGlul and mGlu5 receptor were cultured as described in Hemstapat et al (Mol. Pharmacol. 2006, 70, 616-626).
  • the medium was exchanged from the cells to assay buffer [Hanks’ balanced salt solution (Invitrogen) containing 20 mM HEPES, pH 7.3] using an ELX405 microplate washer (BioTek), leaving 20 pL/well, followed by the addition of 20 pL/well FluoZin2-AM (330 nM final concentration) indicator dye (Invitrogen; prepared as a stock in DMSO and mixed in a 1 : 1 ratio with Pluronic acid F-127) in assay buffer. Cells were incubated for 1 h at room temperature, and the dye exchanged to assay buffer using an ELX405, leaving 20 pL/well.
  • assay buffer [Hanks’ balanced salt solution (Invitrogen) containing 20 mM HEPES, pH 7.3] using an ELX405 microplate washer (BioTek), leaving 20 pL/well, followed by the addition of 20 pL/well FluoZin2-AM (330 nM final concentration) indicator dye (Invitrogen; prepared
  • Test compounds were diluted to 2 times their final desired concentration in assay buffer (0.3% DMSO final concentration). Agonists were diluted in thallium buffer [125 mM sodium bicarbonate (added fresh the morning of the experiment), 1 mM magnesium sulfate, 1.8 mM calcium sulfate, 5 mM glucose, 12 mM thallium sulfate, and 10 mM HEPES, pH 7.3] at 5 times the final concentration to be assayed. Cell plates and compound plates were loaded onto a kinetic imaging plate reader (FDSS 6000 or 7000; Hamamatsu Corporation, Bridgewater, NJ).
  • FDSS 6000 or 7000 Hamamatsu Corporation, Bridgewater, NJ
  • the slope of the fluorescence increase beginning 5 s after thallium/agonist addition and ending 15 s after thallium/agonist addition was calculated, corrected to vehicle and maximal agonist control slope values, and plotted in using either XLfit (ID Business Solutions Ltd) or Prism software (GraphPad Software, San Diego, CA) to generate concentration-response curves. Potencies were calculated from fits using a four-point parameter logistic equation.
  • concentration-response curve experiments compounds were serially diluted 1 :3 into 10-point concentration response curves and were transferred to daughter plates using an Echo acoustic plate reformatter (Labcyte, Sunnyvale, CA). Test compounds were applied and followed by EC20 concentrations of glutamate.

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Abstract

L'invention concerne des modulateurs allostériques positifs (PAM) actifs à petites molécules du récepteur de sous-type-2 et -3 métabotropique du glutamate, des compositions comprenant les composés, et des méthodes d'utilisation des composés et des compositions comprenant les composés.
PCT/US2024/034470 2023-06-20 2024-06-18 Modulateurs allostériques positifs du sous-type-2 et -3 du récepteur métabotropique du glutamate et leurs utilisations Pending WO2024263563A1 (fr)

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WO2011116356A2 (fr) * 2010-03-19 2011-09-22 Sanford-Burnham Medical Research Institute Modulateurs allostériques positifs de mglurs de type 2

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Publication number Priority date Publication date Assignee Title
WO2011116356A2 (fr) * 2010-03-19 2011-09-22 Sanford-Burnham Medical Research Institute Modulateurs allostériques positifs de mglurs de type 2

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* Cited by examiner, † Cited by third party
Title
SIDIQUE, S. ET AL.: "Orally active metabotropic glutamate subtype 2 receptor positive allosteric modulators: structure-activity relationships and assessment in a rat model of nicotine dependence", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 22, 2012, pages 9434 - 9445, XP093173148, DOI: 10.1021/jm3005306 *

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