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WO2015069752A1 - Ligands de protéine de liaison à l'acétylcholine, modulateurs nachr coopérants et procédés de fabrication et d'utilisation - Google Patents

Ligands de protéine de liaison à l'acétylcholine, modulateurs nachr coopérants et procédés de fabrication et d'utilisation Download PDF

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Publication number
WO2015069752A1
WO2015069752A1 PCT/US2014/064104 US2014064104W WO2015069752A1 WO 2015069752 A1 WO2015069752 A1 WO 2015069752A1 US 2014064104 W US2014064104 W US 2014064104W WO 2015069752 A1 WO2015069752 A1 WO 2015069752A1
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substituted
optionally
unsubstituted
group
nachr
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WO2015069752A9 (fr
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Palmer Taylor
Katarzyna Kaczanowska
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University of California Berkeley
University of California San Diego UCSD
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University of California Berkeley
University of California San Diego UCSD
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to a family of compounds that interact with the
  • acetylcholine binding protein and the nicotinic acetylcholine receptor (nAChR) at the subunit interfaces in a cooperative manner. Either through their pre-synaptic or post- 20 synaptic actions, they modulate the release of acetylcholine or importantly other
  • neurotransmitters include the excitatory amino acids such as glutamate or aspartate; the inhibitor amino acids, such as ⁇ -aminobutyric acid (GABA) and glycine;
  • bigenic amines such as norepinephrine, epinephrine, dopamine and serotonin.
  • the invention provides
  • compositions responsive to modulating, decreasing or increasing the activity of an nAChR in the CNS or brain do not resemble acetylcholine structurally, but rather display an unusual cooperative binding interaction involving multiple sites on this pentameric protein. If the pentameric protein is composed of identical subunits, exemplary compounds of the invention can facilitate or inhibit the binding of acetylcholine. If the subunits are not identical, exemplary compounds of the invention can affect acetylcholine binding and stimulation in an allosteric manner.
  • the invention provides compositions and methods for treating, ameliorating, preventing or lessening the symptoms of an tobacco or nicotine-related addiction, e.g., thereby promoting smoking cessation, or a substance abuse, by, e.g., preventing the abstinence syndrome and addiction in two ways; (a) serving as a partial agonist alternative to nicotine; and/or, (b) ameliorating the symptoms of withdrawal and abstinence through their actions on the dopamine and other neurotransmitter systems.
  • the invention provides compositions and methods for treating, ameliorating, preventing or lessening the symptoms of disorders of development of the central nervous system, such as autism, schizophrenia, and other psychosis.
  • disorders of aging such as Alzheimer's diseases Parkinson's disease or psychoses.
  • the invention provides compositions and methods for treating, ameliorating, preventing or lessening the symptoms of disorders of the peripheral nervous system with its sensory afferent and efferent pathways, including treating, ameliorating, preventing or lessening acute and chronic pain, and providing pain relief, including allodynia, including movement, thermal or mechanical allodynia.
  • the invention provides compositions and methods for treating, ameliorating, preventing or lessening the symptoms of any condition responsive to an increase in levels or activity of dopamine in the CNS or brain, or any disease or condition responsive to the modulation of, or a decrease or an increase in the activity of nAChR.
  • AChBP acetylcholine binding protein
  • compounds of the invention also can modulate GABA, glycine and 5-hydroxytryptamine receptors in the CNS.
  • Nicotinic acetylcholine receptors are pentamers, which means that they are formed by five units that can be identical (or homomeric) or have different structures (or be heteromeric). Some proteins that are composed of more than one unit, and therefore have multiple binding sites, exhibit so called
  • nAChR neuropeptide
  • nicotine increases the release of dopamine in the brain, a neurotransmitter that is responsible for feelings of pleasure. In theory, without the nicotine-induced elevation of dopamine levels, tobacco would not produce this type of reward.
  • nAChR nicotinic acetylcholine receptor
  • AChBP acetylcholine binding protein
  • the invention provides compounds that
  • nAChR nicotinic acetylcholine receptor
  • the invention provides methods for formulating or using these compounds to increase or stimulate an nAChR functional response, e.g., to increase dopamine levels or activity.
  • the invention provides compounds,
  • compositions or formulations comprising:
  • Rl, R2, R3 and R4 are independently selected from the group consisting of: a hydrogen, an aryl (wherein optionally the aryl is any 5-or 6-membered ring, or is selected from the group consisting of: a heteroaryl, an aryl halide, a heteroaryl cycloalkyl, a phenyl, a naphthyl, a thienyl, an indolyl, a thiophene, or a isoxasole), an unsubstituted amino or a substituted amino (NRR'), a halo, a hydroxy (-OH), a substituted or an unsubstituted hydroxy (-OR), a phenoxy, a thiol (-SH), a substituted or an unsubstituted thiol (-SR), a cyano (-CN), a formyl (-CHO), a substituted or unsubstituted alkyl (wherein
  • a methyl-aryl substituent a benzylic substituent, an alkenyl, an alkynyl, a cycloalkyl
  • the cycloalkyl is selected from the group consisting of: -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, - cycloheptyl, and - cyclooctyl
  • a cycloalkenyl a substituted alkyl, a substituted alkenyl, a substituted alkynyl, a substituted cycloalkyl, a substituted cycloalkenyl, an aryl, a heteroaryl silyl, a heterosilyl and a heterocyclic group
  • the heterocyclic group is selected from the group consisting of: a saturated heterocyclic and/or a nonsaturated heterocyclic, and optionally the saturated heterocyclic and/or a non-cyclic and a
  • R2 is a substituted amino (NRR', or N-R2-R3) , or
  • Rl is an amino group
  • R2 is a substituted amino (NRR', -R2-R3)
  • R3 is a hydrogen
  • R4 is an aryl group
  • R2 and R3 of Formula II, or Rl and R2 of formula III are independently selected the group consisting of:
  • a hydrogen an aryl (wherein optionally the aryl is any 5-or 6-membered ring, or is selected from the group consisting of: a heteroaryl, an aryl halide, a heteroaryl cycloalkyl, a phenyl, a naphthyl, a thienyl, an indolyl, a thiophene, or a isoxasole), an unsubstituted amino or a substituted amino (NRR'), a halo, a hydroxy (-OH), a substituted or an unsubstituted hydroxy (-OR), a phenoxy, a thiol (-SH), a substituted or an unsubstituted thiol (-SR), a cyano (-CN), a formyl (-CHO), a substituted or unsubstituted alkyl (wherein optionally the alkyl is selected from the group consisting of: - methyl, -
  • a methyl-aryl substituent a benzylic substituent, an alkenyl, an alkynyl, a cycloalkyl
  • the cycloalkyl is selected from the group consisting of: -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, - cycloheptyl, and - cyclooctyl
  • a cycloalkenyl a substituted alkyl, a substituted alkenyl, a substituted alkynyl, a substituted cycloalkyl, a substituted cycloalkenyl, an aryl, a heteroaryl silyl, a heterosilyl and a heterocyclic group
  • the heterocyclic group is selected from the group consisting of: a saturated heterocyclic and/or a nonsaturated heterocyclic, and optionally the saturated heterocyclic and/or a non-cyclic and a
  • X, Y and Z are independently selected from the group consisting of: a C and an N
  • Rl, R2, R3, R4 and R5 of Formula IV are independently selected from the group consisting of:
  • a hydrogen an aryl (wherein optionally the aryl is any 5-or 6-membered ring, or is selected from the group consisting of: a heteroaryl, an aryl halide, a heteroaryl cycloalkyl, a phenyl, a naphthyl, a thienyl, an indolyl, a thiophene, or a isoxasole), an unsubstituted amino or a substituted amino (NRR'), a halo, a hydroxy (-OH), a substituted or an unsubstituted hydroxy (-OR), a phenoxy, a thiol (-SH), a substituted or an unsubstituted thiol (-SR), a cyano (-CN), a formyl (-CHO), a substituted or unsubstituted alkyl (wherein optionally the alkyl is selected from the group consisting of: - methyl, -
  • a halogen a methyl-aryl substituent, a benzylic substituent, an alkenyl, an alkynyl, a cycloalkyl
  • the cycloalkyl is selected from the group consisting of: -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, - cycloheptyl, and - cyclooctyl
  • a cycloalkenyl a substituted alkenyl, a substituted alkynyl, a substituted cycloalkyl, a substituted cycloalkenyl, a heteroaryl silyl, a heterosilyl and a heterocyclic group
  • the heterocyclic group is selected from the group consisting of: a saturated heterocyclic and/or a nonsaturated heterocyclic, and optionally the saturated heterocyclic and/or a nonsaturated heterocyclic is
  • X, Y and Z are independently selected from the group consisting of: a C an N, an O and an S,
  • Rl, R2, R3 and R4, of Formula V are independently selected from the group consisting of: a hydrogen, an aryl (wherein optionally the aryl is any 5-or 6-membered ring, or is selected from the group consisting of: a heteroaryl, an aryl halide, a heteroaryl cycloalkyl, a phenyl, a naphthyl, a thienyl, an indolyl, a thiophene, or a isoxasole), an unsubstituted amino or a substituted amino (NRR'), a halo, a hydroxy (-OH), a substituted or an unsubstituted hydroxy (-OR), a phenoxy, a thiol (-SH), a substituted or an unsubstituted thiol (-SR), a cyano (-CN), a formyl (-CHO), a substituted or unsubstituted alkyl (
  • a halogen a methyl-aryl substituent, a benzylic substituent, an alkenyl, an alkynyl, a cycloalkyl
  • the cycloalkyl is selected from the group consisting of: -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, - cycloheptyl, and - cyclooctyl
  • a cycloalkenyl a substituted alkyl, a substituted alkenyl, a substituted alkynyl, a substituted cycloalkyl, a substituted cycloalkenyl, an aryl, a heteroaryl silyl, a heterosilyl and a heterocyclic group
  • the heterocyclic group is selected from the group consisting of: a saturated heterocyclic and/or a nonsaturated heterocyclic, and optionally the saturated heterocyclic
  • nAChR nicotinic acetylcholine receptor
  • acetylcholine ligand- acetylcholine receptor response has a positive or a negative cooperativity in an acetylcholine ligand- acetylcholine receptor response, or in ligand occupation of the acetylcholine binding protein (AChBP), or
  • nAChR nicotinic acetylcholine receptor
  • the invention provides products of manufacture or a device capable of injecting, causing inhalation of, adsorption of, or otherwise designed for administering for either enteral or parenteral administration: a compound, composition or formulation of the invention to an individual in need thereof, wherein optionally the product of manufacture or a device comprises: a compound, composition or formulation of the invention.
  • the compound, composition or formulation of the invention is formulated for administration in vivo; or for enteral or parenteral administration, or for oral, ophthalmic, topical, oral, intravenous (IV), intramuscular (IM), intrathecal, subcutaneous (SC), intracerebral, epidural, intracranial or rectal administration, or by inhalation.
  • IV intravenous
  • IM intramuscular
  • SC subcutaneous
  • intracerebral epidural
  • intracranial or rectal administration or by inhalation.
  • the compound, composition or formulation is formulated as: a particle, a nanoparticle, a liposome, a tablet, a pill, a capsule, a gel, a geltab, a liquid, a powder, a suspension, a syrup, an emulsion, a lotion, an ointment, an aerosol, a spray, a lozenge, an ophthalmic preparation, an aqueous or a sterile or an injectable solution, a patch (optionally a transdermal patch or a medicated adhesive patch), or an implant.
  • the invention provides pharmaceutical compositions or formulations comprising a compound, composition or formulation of the invention, wherein optionally the pharmaceutical composition or formulation further comprises a pharmaceutically acceptable excipient.
  • the invention provides products of manufacture or a device, comprising a compound, composition or formulation of the invention, or a pharmaceutical composition or formulation of the invention, wherein optionally the product of manufacture or device is a medical device or an implant, wherein optionally the product of manufacture or device is designed to be capable of injecting, causing inhalation of, adsorption of, or otherwise administering for either enteral or parenteral administration a compound, composition or formulation of the invention, or a pharmaceutical composition or formulation of the invention.
  • the invention provides a pump, a patch, a device, a subcutaneous infusion device, a continuous subcutaneous infusion device, a pen, an infusion pen, a needle, a reservoir, an ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi-chambered pump, comprising a compound, composition or formulation of the invention, or a pharmaceutical composition or formulation of the invention.
  • the invention provides methods for
  • nAChR nicotinic acetylcholine receptor
  • nAChR nicotinic acetylcholine receptor
  • acetylcholine ligand- acetylcholine receptor response having a positive or a negative cooperativity in an acetylcholine ligand- acetylcholine receptor response, or in ligand occupation of the acetylcholine binding protein (AChBP), or
  • nAChR nicotinic acetylcholine receptor
  • a device comprising contacting the AChR with a compound, composition or formulation of the invention, or administering to an individual in need thereof a product of manufacture or a device of the invention, or a or a pump, a patch, a device, a subcutaneous infusion device, a continuous subcutaneous infusion device, a pen, an infusion pen, a needle, a reservoir, an ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi-chambered pump of the invention, thereby
  • nAChR nicotinic acetylcholine receptor
  • nAChR nicotinic acetylcholine receptor
  • AChBP acetylcholine binding protein
  • nAChR nicotinic acetylcholine receptor
  • the contacting is in vitro, ex vivo or in vivo.
  • the invention provides methods for increasing, modulating or stimulating the release of or activity of a neurotransmitter or a
  • nAChR nicotinic acetylcholine receptor
  • the neurotransmitter or a neuromodulator comprises a glutamate, a gamma aminobutyric acid (GABA), a glycine, a serotonin, a peptide or a neuropeptide (optionally a galanin, an enkephalin, an acetylcholine), a norepinephrine, or a biogenic amine (optionally a dopamine, a noradrenaline, an adrenaline, or a
  • GABA gamma aminobutyric acid
  • a pump comprising: administering to an individual in need thereof a compound, composition or formulation of the invention, or a pharmaceutical composition or formulation of the invention, or administering to an individual in need thereof a product of manufacture or a device of the invention, or a pump, a patch, a device, a subcutaneous infusion device, a continuous subcutaneous infusion device, a pen, an infusion pen, a needle, a reservoir, an ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi-chambered pump of the invention,
  • nAChR nicotinic acetylcholine receptor
  • the contacting is in vitro, ex vivo or in vivo.
  • the invention provides methods for treating, ameliorating, preventing or lessening the symptoms of diseases or conditions that are responsive to modulating, decreasing or increasing levels or activity of a neurotransmitter or a neuromodulator in the CNS or brain, or are responsive to modulating, decreasing or increasing the activity of a nicotinic acetylcholine receptor (nAChR) in the CNS or brain, wherein optionally the neurotransmitter or a neuromodulator comprises a glutamate, a gamma aminobutyric acid (GABA), a glycine, a serotonin, a peptide or a neuropeptide (optionally a galanin, an enkephalin, an acetylcholine), a norepinephrine, or a biogenic amine (optionally a dopamine, a noradrenaline, an adrenaline, or a catecholamine), comprising:
  • a pump comprising: administering to an individual in need thereof a compound, composition or formulation of the invention, or a pharmaceutical composition or formulation of the invention, or administering to an individual in need thereof a product of manufacture or a device of the invention, or a pump, a patch, a device, a subcutaneous infusion device, a continuous subcutaneous infusion device, a pen, an infusion pen, a needle, a reservoir, an ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi-chambered pump of the invention,
  • nAChR nicotinic acetylcholine receptor
  • the contacting is in vitro, ex vivo or in vivo.
  • the invention provides methods for treating, ameliorating, preventing or lessening the symptoms of an addiction or substance abuse, optionally an addiction or substance abuse involving use of tobacco or nicotine-related products, involving modulating, decreasing or increasing levels or activity of a neurotransmitter or a neuromodulator in the CNS or brain, or responsive to modulating, decreasing or increasing the activity of a nicotinic acetylcholine receptor (nAChR) in the CNS or brain,
  • nAChR nicotinic acetylcholine receptor
  • the neurotransmitter or a neuromodulator comprises a glutamate, a gamma aminobutyric acid (GABA), a glycine, a serotonin, a peptide or a neuropeptide (optionally a galanin, an enkephalin, an acetylcholine), a norepinephrine, or a biogenic amine (optionally a dopamine, a noradrenaline, an adrenaline, or a catecholamine), or for treating, ameliorating, preventing or lessening the symptoms of an addiction or substance abuse involving tobacco or nicotine use, cigarette smoking, methylphenidate, cocaine, or amphetamines or methamphetamines, or 3,4-methylenedioxy-N- methylamphetamine (MDMA), comprising:
  • a pharmaceutical composition or formulation of the invention a product of manufacture or a device of the invention, or a pump, a patch, a device, a subcutaneous infusion device, a continuous subcutaneous infusion device, a pen, an infusion pen, a needle, a reservoir, an ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi-chambered pump of the invention,
  • an addiction or substance abuse optionally an addiction or substance abuse involving use of tobacco or nicotine-related products, involving modulating, decreasing or increasing levels or activity of a neurotransmitter or a neuromodulator in the CNS or brain, or responsive to modulating, decreasing or increasing the activity of a nicotinic
  • acetylcholine receptor in the CNS or brain, or treating, ameliorating, preventing or lessening the symptoms of an addiction or substance abuse involving tobacco or nicotine use, cigarette smoking, methylphenidate, cocaine, or amphetamines or methamphetamines, or 3,4-methylenedioxy-N-methylamphetamine (MDMA),
  • the contacting is in vitro, ex vivo or in vivo.
  • the invention provides methods for treating, ameliorating, preventing or lessening the symptoms of a disease or condition responsive to an increase in levels or activity of a neurotransmitter or a neuromodulator in the peripheral nervous system (PNS), the central nervous system (CNS) or brain, or a disease or condition responsive to the modulation of, or a decrease or an increase in the activity of a nicotinic acetylcholine receptor (nAChR), or treating, ameliorating, preventing or lessening the symptoms of a dementia, Parkinson's disease, pain or chronic pain, an allodynia, a psychosis, autism, or a schizophrenia,
  • PNS peripheral nervous system
  • CNS central nervous system
  • nAChR nicotinic acetylcholine receptor
  • the neurotransmitter or a neuromodulator comprises a glutamate, a gamma aminobutyric acid (GABA), a glycine, a serotonin, a peptide or a neuropeptide (optionally a galanin, an enkephalin, an acetylcholine), a norepinephrine, or a biogenic amine (optionally a dopamine, a noradrenaline, an adrenaline, or a
  • GABA gamma aminobutyric acid
  • a pharmaceutical composition or formulation of the invention comprising: administering to an individual in need thereof a compound, composition or formulation of the invention, or administering or applying to an individual in need thereof: a pharmaceutical composition or formulation of the invention; a product of manufacture or a device of the invention, or a pump, a patch, a device, a subcutaneous infusion device, a continuous subcutaneous infusion device, a pen, an infusion pen, a needle, a reservoir, an ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi-chambered pump of the invention,
  • a disease or condition responsive to an increase in levels or activity of a neurotransmitter or a neuromodulator in the peripheral nervous system (P S), the central nervous system (CNS) or brain, or a disease or condition responsive to the modulation of, or a decrease or an increase in the activity of a nicotinic acetylcholine receptor (nAChR), or treating, ameliorating, preventing or lessening the symptoms of a dementia, Parkinson's disease, pain or chronic pain, an allodynia, a psychosis, autism, or a schizophrenia,
  • P S peripheral nervous system
  • CNS central nervous system
  • nAChR nicotinic acetylcholine receptor
  • the contacting is in vitro, ex vivo or in vivo.
  • kits comprising a compound, composition or formulation of the invention, a product of manufacture or a device of the invention, and/or optionally comprising ingredients and/or instructions for practicing a method of the invention.
  • the invention provides kits comprising a compound, composition or formulation of the invention, a product of manufacture or a device of the invention, and/or optionally comprising ingredients and/or instructions for practicing a method of the invention.
  • kits comprising a compound, composition or formulation of the invention; a pharmaceutical composition or formulation of the invention; a product of manufacture or a device of the invention, or a pump, a patch, a device, a subcutaneous infusion device, a continuous subcutaneous infusion device, a pen, an infusion pen, a needle, a reservoir, an ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi- chambered pump of the invention, and/or optionally comprising ingredients and/or instructions for practicing a method of the invention.
  • the invention provides uses of a compound, composition or formulation of the invention, in the manufacture of a medicament.
  • the invention provides uses of a compound, composition or formulation of the invention, in the manufacture of a medicament for:
  • nAChR nicotinic acetylcholine receptor
  • nAChR nicotinic acetylcholine receptor
  • nAChR nicotinic acetylcholine receptor
  • neurotransmitter or a neuromodulator in the central nervous system (CNS) or the brain or modulating, decreasing or increasing the activity of a nicotinic acetylcholine receptor (nAChR) in the CNS or brain,
  • nAChR nicotinic acetylcholine receptor
  • nAChR nicotinic acetylcholine receptor
  • nAChR nicotinic acetylcholine receptor
  • PNS peripheral nervous system
  • CNS nicotinic acetylcholine receptor
  • the invention provides therapeutic combinations comprising: a compound, composition or formulation of the invention: a pharmaceutical composition or formulation of the invention; a product of manufacture or a device of the invention, or a pump, a patch, a device, a subcutaneous infusion device, a continuous subcutaneous infusion device, a pen, an infusion pen, a needle, a reservoir, an ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi- chambered pump of the invention.
  • Figure 1A in table form, and Figure IB and Figure 1C in graphic form, summarizes Ki and slope (Hill coefficient, nn) data from radioligand binding
  • Figure 2A schematically illustrates three exemplary synthetic pathways of the invention to generate exemplary 2,4,6-substituted pyrimidine compounds of the invention; as discussed in detail in Example 1, below.
  • Fig. 2B schematically illustrates exemplary compounds of the invention that were synthesized and screened; as discussed in detail in Example 1, below.
  • Figure 2C graphically illustrates the results of quick screen results of the so-called "KK-169 analog" exemplary compounds of the invention, including exemplary compounds of the invention KK 301-A, KK 301-B, KK 302, KK 303, KK 304-A, KK 304-B and KK 305 (see Figure 4, for structures); as discussed in detail in Example 1, below.
  • Figure 3 A schematically illustrates an exemplary compound of the invention, and graphically illustrates the results of an ⁇ 4 ⁇ 2 nAChR agonist screening of a collection of 80 compounds using cell-based medium throughput fluorescence assays, which identified one exemplary compound of the invention, the so-called "KK-253B", that acted as a ⁇ 4 ⁇ 2 nAChR agonist and did not activate a7 nAChR; as discussed in detail in Example 1, below.
  • Figure 3B schematically illustrates exemplary compounds of the invention identified using cell-based assay as ⁇ 4 ⁇ 2 nAChR antagonists; as discussed in detail in Example 1, below.
  • Figure 5 graphically illustrates data from titration curves using radioligand binding assay for the 4,6 substituted 2-aminopyrimidines showing the range of potencies and Hill coefficients for ligand binding:
  • Fig. 5A graphically illustrates data showing that if the binding of ligand at one site lowers the affinity for ligand at another site on an adjacent subunit, the protein exhibits negative cooperativity or induced site heterogeneity, n H ⁇ 1;
  • Fig. 5C graphically illustrates data showing that if the binding of ligand at one site increases the affinity for ligand at another site, the macromolecule exhibits positive cooperativity (nn >1); as discussed in detail in Example 1, below.
  • FIG. 6A schematically illustrates an exemplary scintillation proximity screening scheme of the invention comprising screening of a compound library by a radioligand binding assay against AChBPs; this screen assay resulted in the identification of several additional exemplary compounds of this invention, more so-called “lead structures", with low micromolar affinities; and from these exemplary compounds, or “leads", approximately 40 exemplary compounds, or analogs, were identified, synthesized and screened, as illustrated in Figure 6B.
  • Figure 6B graphically illustrates, and Figure 6C in table form illustrates, radioligand screening results of the pyrimidine series against Lymnea AChBP, where the compounds marked in green (or the so-called "AC" fraction, the middle of the 3 fractions) also have low micromolar Kd values for Aplysia AChBP; as discussed in detail in Example 1, below.
  • Figure 7 schematically illustrates the crystal structure of Ls AChBP-ligand complex: Fig. 7A schematically illustrates a side image, and Fig. 7B
  • FIG. 7C schematically illustrates ligands having n H ⁇ l for both
  • Fig. 7D schematically illustrates n H ⁇ l and n H >l images superimposed; as discussed in detail in Example 1, below.
  • Figure 8 graphically illustrates data from representative titration profiles for 4,6-substituted 2-aminopyrimidine (exemplary compounds of the invention, see Table 4 to associate numbering with structure) competition with 3 H- epibatidine binding showing a range of dissociation constants (K d ) and Hill coefficients (n H ) for ligand binding to Zs-AChBP; as discussed in detail in Example 2, below.
  • Figure 9 shows X-ray crystal structures of exemplary compounds of the invention (ligands) 32 and 33 (negative cooperativity, n H ⁇ l) and exemplary compound 15 (positive cooperativity, n H >l), in complexes with Zs-AChBP:
  • FIG. 9(C) illustrates overlay of exemplary compound 32 (blue) and exemplary compound 33 (yellow) crystal structures; and, Fig 9(D): illustrates a superimposition of exemplary compound 15 (yellow) and exemplary compound 10 33 (blue) crystal structures; as discussed in detail in Example 2, below.
  • Figure 10 shows the superimposition of Zs-AChBP X-ray crystal structures in complex with exemplary compound 33 (Fig. 10A) and exemplary compound 15 (Fig. 10B) with nicotine; as discussed in detail in Example 2, below.
  • Figure 11 shows the global differences in X-ray crystal structures of Ls-
  • FIG. 1 1(A) schematically illustrates a top (apical) view on superimposed (UCSF chimera) Apo pentamer (in blue) and with bound exemplary compound 15 (in red), dashed lines (blue and red respectively) indicate 0 most significant differences in quaternary structures quantified by measuring distances between T13 backbone alpha carbon of distant subunits;
  • Fig. 1 1(B) schematically illustrates a superimposition (PyMOL) of Zs-AChBP Apo, chain D (in blue) and exemplary compound 15 complex, chain D (in red);
  • Figure 12 shows a comparison of Zs-AChBP quaternary changes
  • Fig. 12(A) schematically illustrates an overlay of Ls- AChBP crystal structure in its Apo form
  • Fig. 12(B) illustrates a chart representing 'bloom'
  • x axis delta distance between C a observed in Zs-AChBP - ligand complexes when compared with Zs-AChBP Apo form
  • y axis relative distance from the protein vestibule
  • Fig. 12(A) schematically illustrates an overlay of Ls- AChBP crystal structure in its Apo form
  • Fig. 12(B) illustrates a chart representing 'bloom'
  • x axis delta distance between C a observed in Zs-AChBP - ligand complexes when compared with Zs-AChBP Apo form
  • y axis relative distance from the protein vestibule
  • Fig. 12(A) schematically illustrates an overlay of Ls- AChBP crystal structure in its Apo form
  • Fig. 12(B) illustrates a chart representing
  • FIG. 12(C) illustrates a chart representing 'twist' of the pentameric structure
  • x axis delta dihedral angle between C a observed in Zs-AChBP - ligand complexes when compared with Zs-AChBP Apo form; as discussed in detail in Example 2, below.
  • Figure 14 illustrates Table 6, showing data of competition between exemplary compounds of the invention (numbering corresponds to Table 4 compound numbers) as substituted 2-aminopyrimidines against 3 H-epibatidine binding to Zs-AChBP; as discussed in detail in Example 2, below.
  • Figure 15 schematically illustrates an overlay of exemplary compound 15 (yellow) and exemplary compound 32 (blue) crystal structures;
  • Fig. 15(B) schematically illustrates superimposition of exemplary compound 15
  • Figure 16 illustrates a screening assay demonstrating activity of exemplary compounds of the invention (so-called compounds 17, KK-311-D and 171 A, see Table 4 for structures), using activation of a7-nAChr CNiFERS with l-(5-chloro- 2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl);
  • Fig. 16A and Fig. 16B graphically illustrates the results at 50 uM and 10 uM concentrations
  • Fig. 15C graphically illustrates these results; as discussed in detail in Example 2, below.
  • Figure 17 schematically illustrates three (1, 2, 3) exemplary synthetic pathways of the invention to generate exemplary 2,4,6-substituted pyrimidine compounds of the invention, including the so-called Formula I genus structure; as discussed in detail in Example 2, below.
  • Figure 18 schematically illustrates exemplary synthetic pathways of the invention to generate exemplary 2,4,5 -substituted pyrimidine compounds of the invention, including the so-called Formula I genus structure; as discussed in detail in Example 2, below.
  • Like reference symbols in the various drawings indicate like elements.
  • the invention provides compounds and
  • compositions that are selective ligands to acetylcholine binding protein (AChBP) and have unique properties.
  • AChBP acetylcholine binding protein
  • these AChBP ligands have both negative as well as positive
  • This invention for the first time describes cooperative binding activity by the acetylcholine binding protein (AChBP), compounds and compositions that can modulate this cooperative binding activity. Since AChBP only consists of the extracellular domain of the nAChR, compounds of the invention uniquely show that cooperativity, be it negative or positive, can occur in a circumferential
  • this invention widens the structural base for achieving selectivity with the nAChR.
  • the structures of exemplary compounds of the invention depart substantially from structures of the classical agonists and antagonists of the nAChR.
  • the invention establishes a previously-unknown level of conformational communication of AChBP subunits upon ligand binding. Interaction of a ligand in the first binding pocket causes structural changes between subunits resulting in a transition between different affinity states. In case of negative cooperativity, the unoccupied site in the pentamer becomes structurally restrained, leading to reduced affinity for binding of the second ligand. By translating the phenomena to nicotinic receptors, ligands
  • receptors e.g., nicotinic and ligand gated ion channel
  • compositions and formulations of the present disclosure are provided in alternative embodiments.
  • inventions act as ligands that bind cooperatively to the acetylcholine binding
  • compositions and methods are described in detail below.
  • compositions and formulations of the invention have relatively high affinities, or low dissociation constants - particularly for the negatively cooperative ligands.
  • compositions and formulations of the invention cause
  • conformational changes in the acetylcholine binding protein that are seen globally in the protein; these conformational changes are unique to the 2-aminopyrimidines that are not seen in the classical agonists (for example, nicotine or epibatidine) or antagonists (for example, benzylidene anabaseine,
  • compositions and formulations of the invention can stimulate the alpha-7 nicotinic receptor, thus acting as drugs or pharmaceutically active reagents.
  • the invention provides exemplary compounds of the invention as "congeneric structures" that exhibit cooperativity, where many members of the family show Hill slopes greater than 1.0 or considerably less than 1.0. The latter is not due to heterogeneity of the binding protein template, since AChBP has five identical sites as examined crystallographically and by conventional ligand binding. These cooperative interactions appear not to require a direct connection with the channel gating area to elicit subunit interactions and cooperativity. Rather, cooperativity can be confined to the extra-cellular domain and is mediated circumferentially around the cylindrical pentamer. This unique feature of compounds of the invention, these AChBP ligands, makes them effective as medications with distinct pharmacological profiles.
  • Figure 4 illustrates generic structures of the invention in cooperative series 1; structure of most potent ligands, 4,6-substituted 2-amino pyrimidines 2.
  • the invention provides compounds that
  • nAChR nicotinic acetylcholine receptor
  • exemplary compounds of the invention can stimulate a nAChR functional response.
  • the invention provides two
  • types (or classes or genuses) of exemplary compounds one class (or type or
  • nAChR binding proteins binds in a cooperative manner to nAChR binding proteins, and a second exemplary class (or type or genus) activates a functional response of an nAChR by its binding.
  • both classes of compounds of the invention can increase the release of dopamine in the CNS or brain, or increase the activity of nAChR in the CNS or brain.
  • the invention provides compounds, compositions and methods for increasing or stimulating the release of or activity of dopamine in the central nervous system (CNS), including the brain, or increasing the activity of nAChR in the CNS or brain, and compounds, compositions and methods for treating, ameliorating, preventing or lessening the symptoms of diseases or conditions that are responsive to an increase in levels or activity of dopamine in the CNS or brain, or responsive to an increase in the activity of nAChR in the CNS or brain.
  • CNS central nervous system
  • the invention provides compounds, compositions and methods for treating, ameliorating, preventing or lessening the symptoms of an addiction or substance abuse involving increasing levels or activity of dopamine in the CNS or brain, or responsive to an increase in the activity of nAChR in the CNS or brain, for example, for treating, ameliorating, preventing or lessening the symptoms of an addiction or a substance abuse, e.g., an addiction or a substance abuse involving cigarette smoking, methylphenidate, cocaine, or amphetamines or methamphetamines, such as 3,4-methylenedioxy-N-methylamphetamine
  • the invention provides compounds, compositions and methods for treating, ameliorating, preventing or lessening the symptoms of a disease or condition responsive to an increase in levels or activity of dopamine in the CNS or brain, or responsive to an increase in the activity of nAChR in the CNS or brain, for example, dementia, Parkinson's disease, pain or chronic pain, allodynia, autism, psychosis or schizophrenia.
  • the invention also provides bioisosteres of compounds of the invention, e.g., compounds having a structure as set forth in Table 1, Table 2, Table 3 or Table 4.
  • bioisosteres of the invention are compounds of the invention comprising one or more substituent and/or group replacements with a substituent and/or group having substantially similar physical or chemical properties which produce substantially similar
  • the purpose of exchanging one bioisostere for another is to enhance the desired biological or physical properties of a
  • bioisosteres of compounds of the disclosure are provided.
  • bioisosteres of compounds of the disclosure are provided.
  • inventions are made by replacing one or more hydrogen atom(s) with one or more fluorine atom(s), e.g., at a site of metabolic oxidation; this may prevent
  • the molecule may have a blocked pathway for metabolism
  • the invention provides compounds and compositions, including formulations and pharmaceutical compositions, for use in in vivo, in vitro or ex vivo methods, e.g., for:
  • an addiction or substance abuse e.g., an addiction or substance abuse involving cigarette smoking, methylphenidate, cocaine, or amphetamines or methamphetamines, or 3,4- methylenedioxy-N-methylamphetamine (MDMA)
  • an addiction or substance abuse e.g., an addiction or substance abuse involving cigarette smoking, methylphenidate, cocaine, or amphetamines or methamphetamines, or 3,4- methylenedioxy-N-methylamphetamine (MDMA)
  • a dementia for treating, ameliorating, preventing or lessening the symptoms of a dementia, Parkinson's disease, pain or chronic pain, allodynia, autism, psychosis or schizophrenia.
  • compositions of the invention can be administered parenterally, topically, orally or by local administration, such as by aerosol or transdermally.
  • pharmaceutical compositions can be prepared in various forms, such as granules, tablets, pills, capsules, suspensions, taken orally, suppositories and salves, lotions and the like.
  • Pharmaceutical formulations of this invention may comprise one or more diluents, emulsifiers, preservatives, buffers, excipients, etc.
  • the pharmaceutical compounds can be delivered by
  • transdermally by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • compositions of the invention are delivered orally, e.g., as pharmaceutical formulations for oral administration, and can be formulated using pharmaceutically acceptable carriers well known in the art in appropriate and suitable dosages.
  • Such carriers enable the pharmaceuticals to be formulated in unit dosage forms as tablets, pills, powder, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient.
  • Oral carriers can be elixirs, syrups, capsules, tablets, pills, geltabs and the like.
  • compositions for oral use can be formulated as a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable additional compounds, if desired, to obtain tablets or dragee cores.
  • suitable solid excipients are carbohydrate or protein fillers include, e.g., sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose,
  • liquid carriers are used to manufacture or formulate compounds of this invention, or a composition used to practice the methods of this invention, including carriers for preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid carrier can comprise other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • solid carriers are used to manufacture or formulate compounds of this invention, or a composition used to practice the methods of this invention, including solid carriers comprising substances such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like.
  • a solid carrier can further include one or more substances acting as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
  • the carrier can be a finely divided solid which is in admixture with the finely divided active compound.
  • the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • compounds and pharmaceutical compositions of the invention are formulated as and/or delivered as patches, e.g., a transdermal patch or a medicated adhesive patch that is placed on the skin or mucous membrane to deliver a specific dose of drug or medication (e.g., compounds and pharmaceutical compositions of the invention) through the skin and into the bloodstream.
  • a transdermal drug delivery route over other types of medication delivery such as oral, topical, intravenous, intramuscular, etc. can be that the patch provides a controlled release of the drug or medication into the patient, optionally through either a porous membrane covering a reservoir of medication or through body heat melting thin layers of medication embedded in the adhesive.
  • a patch is a single-layer drug-in-adhesive patch; in this exemplary embodiment, the adhesive layer also contains the drug or medication (e.g., compounds and pharmaceutical compositions of the invention).
  • the adhesive layer can not only serves to adhere the various layers together, along with the entire system to the skin, but also can be responsible for the releasing of the drug or medication.
  • the adhesive layer can be surrounded by a temporary liner and a backing.
  • a patch is a multi-layer drug-in- adhesive patch, which is similar to the single-layer system, but it adds another layer of drug-in-adhesive, optionally separated by a membrane.
  • One of the layers can be for immediate release of a drug or medication (e.g., compounds and pharmaceutical compositions of the invention) and other layer is for control release of the same and/or different drug or medication from the reservoir.
  • This patch also can have a temporary liner-layer and a permanent backing.
  • drug release depends on membrane permeability and diffusion of drug molecules.
  • a patch is a reservoir transdermal system, which has a separate drug layer; the drug layer can be a liquid or gel compartment comprising a drug solution or a suspension separated by the adhesive layer.
  • the drug reservoir can be totally encapsulated in a shallow compartment molded from a drug-impermeable metallic plastic laminate, optionally with a rate-controlling membrane made of a polymer (e.g., a vinyl acetate) on one surface.
  • This patch also can be backed by a backing layer.
  • the rate of release can be designed to be zero order.
  • a patch is a matrix system, or so-called “monolithic device", which comprises a drug layer of a solid or a semisolid matrix comprising a drug solution or a suspension (e.g., comprising compounds and pharmaceutical compositions of the invention).
  • the adhesive layer in this patch can surround the drug layer, optionally partially overlaying it.
  • compounds and pharmaceutical compositions of the invention are formulated as and/or delivered as or in so-called "thin-film” or dissolving film delivery systems. These can be used to administer a drug solution or a suspension (e.g., comprising compounds and pharmaceutical compositions of the invention) via absorption in the mouth (e.g., buccally or sublingually) and/or via the small intestines or otherwise enterically.
  • a film can be prepared using a hydrophilic polymer that rapidly dissolves on a mucous membrane, e.g., in the tongue or buccal cavity or esophagus or intestine, thus delivering the drug to the systemic circulation via dissolution when contact with liquid (e.g., a bodily fluid) is made.
  • thin-film drug delivery is used as an alternative to or with another delivery modality, e.g., tablets, capsules, liquids and the like. They can be similar in size, shape and thickness to a postage stamp, and can be designed for oral administration, with the user placing the strip on or under the tongue (sublingual) or along the inside of the cheek (buccal). As the strip dissolves, the drug can enter the blood stream enterically, buccally or sublingually.
  • thin-films are made of combination of microcrystalline cellulose and maltodextrin, and can also include plasticizers, phthalate, glycols.
  • concentrations of therapeutically active compound in a formulation can be from between about 0.1% to about 100%, e.g., having at least about 0.5%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%, or more, by weight.
  • therapeutic formulations are prepared by any method well known in the art, e.g., as described by Brunton et al, eds., Goodman and Gilman's: The Pharmacological Bases of Therapeutics , 12th ed., McGraw-Hill, 201 1; Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20th ed., 2000; Avis et al, eds., Pharmaceutical Dosage Forms: Parenteral Medications, published by Marcel Dekker, Inc., N.Y., 1993; Lieberman et al, eds., Pharmaceutical Dosage Forms: Tablets, published by Marcel Dekker, Inc., N.Y., 1990; and Lieberman et al., eds., Pharmaceutical Dosage Forms: Disperse Systems, published by Marcel Dekker, Inc., N.Y., 1990.
  • therapeutic formulations are delivered by any effective means appropriated for a particular treatment.
  • the suitable means include oral, rectal, vaginal, nasal, pulmonary administration, or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) infusion into the bloodstream.
  • parenteral administration antitumor agents of the present invention may be formulated in a variety of ways.
  • Aqueous solutions of the modulators can be encapsulated in polymeric beads, liposomes, nanoparticles or other injectable depot formulations known to those of skill in the art.
  • compounds of the invention are administered encapsulated in liposomes.
  • compositions are present both in an aqueous layer and in a lipidic layer, e.g., a liposomic suspension.
  • a hydrophobic layer comprises phospholipids such as lecithin and sphingomyelin, steroids such as cholesterol, more or less ionic surfactants such a diacetylphosphate, stearylamine, or phosphatidic acid, and/or other materials of a hydrophobic nature.
  • compositions can be formulated in any way and can be administered in a variety of unit dosage forms depending upon the condition or disease and the degree of illness, the general medical condition of each patient, the resulting preferred method of administration and the like.
  • an exemplary dosage may be about 30 mg/kg administered e.g., by intravenous therapy, e.g., over between about 15 to 30 minutes, or by intramuscular injection or subcutaneous injection, e.g., repeated later in intervals, e.g., at about 60 minutes later.
  • intravenous therapy e.g., over between about 15 to 30 minutes
  • intramuscular injection or subcutaneous injection e.g., repeated later in intervals, e.g., at about 60 minutes later.
  • an exemplary dosage and administration is as a 500 mg/h continuous IV infusion.
  • an exemplary dosage and administration is as a 500 mg/h continuous IV infusion.
  • an exemplary dosage and administration is as a 500 mg/h continuous IV infusion.
  • administration is at between about 20 to 50 mg/kg, optionally followed by a maintenance infusion at between about 5 to 10 mg/kg/h.
  • an exemplary dosage and administration is based on long term, low dosage administration, for example, by a slow release pharmaceutical vehicle, or by slow release from an implant.
  • compositions of the invention are formulated in a buffer, in a saline solution, in a powder, an emulsion, in a vesicle, in a liposome, in a
  • compositions can be formulated in any way and can be applied in a variety of concentrations and forms depending on the desired in vivo, in vitro or ex vivo conditions, a desired in vivo, in vitro or ex vivo method of administration and the like. Details on techniques for in vivo, in vitro or ex vivo formulations and administrations are well described in the scientific and patent literature. Formulations and/or carriers used to practice this invention can be in forms such as tablets, pills, powders, capsules, liquids, gels, syrups, slurries, suspensions, etc., suitable for in vivo, in vitro or ex vivo
  • the compounds (e.g., formulations) of the invention can comprise a solution of compounds of the invention, including stereoisomers, derivatives and analogs thereof, disposed in or dissolved in a pharmaceutically acceptable carrier, e.g., acceptable vehicles and solvents that can be employed include water and Ringer's solution, an isotonic sodium chloride.
  • a pharmaceutically acceptable carrier e.g., acceptable vehicles and solvents that can be employed include water and Ringer's solution, an isotonic sodium chloride.
  • sterile fixed oils can be employed as a solvent or suspending medium.
  • any fixed oil can be employed including synthetic mono- or diglycerides, or fatty acids such as oleic acid.
  • solutions and formulations used to practice the invention are sterile and can be manufactured to be generally free of undesirable matter. In one embodiment, these solutions and formulations are sterilized by conventional, well known sterilization techniques.
  • solutions and formulations used to practice the invention can comprise auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.
  • concentration of active agent in these formulations can vary widely, and can be selected primarily based on fluid volumes, viscosities and the like, in accordance with the particular mode of in vivo, in vitro or ex vivo administration selected and the desired results.
  • compositions and formulations of the invention can be delivered by the use of liposomes.
  • liposomes particularly where the liposome surface carries ligands specific for target cells or organs, or are otherwise preferentially directed to a specific tissue or organ type, one can focus the delivery of the active agent into a target cells in an in vivo, in vitro or ex vivo application.
  • compositions and formulations of the invention can be directly administered, e.g., under sterile conditions, to an individual (e.g., a patient) to be treated.
  • the modulators can be administered alone or as the active ingredient of a pharmaceutical composition.
  • Compositions and formulations of this invention can be combined with or used in association with other therapeutic agents. For example, an individual may be treated concurrently with conventional therapeutic agents.
  • a compound, a formulation or mixture of compounds of the invention is/are administered parenterally in an appropriate co-solvent to enable distribution from the site of IM, SC or IV injection, to prevent post- injection precipitation by virtue of a change in pH, for example, as described in J. Pharm. Pharmacol: 62:873-82 (2010); Adv. Drug Delivery Rev. 59:603-07 (2007), and to ensure "solubilization" conditions at the injection site, e.g., as described in J. Pharm. Pharmacol 62: 1607-21; Anesth Analg 79: 933-39 (1994); J. Pharm. Pharmacol 65 1429-39 (2013).
  • the compounds of the invention can be administered at low pH (e.g., between about pH 4 to 6) or high pH (e.g., between about pH 8 to 11).
  • these alternative embodiments involve: Low pH solutions adjusted with acetic acid; High pH solutions adjusted with a 2 C0 3 (pH 10- 11); Co-solvent formulation at neutral pH to include propylene glycol (up to 50%), polyethylene glycol, 2-hydroxypropyl ⁇ -cyclodextrin and combinations and congeners thereof; and/or, micellular dispersions with surface active agents.
  • oral (p.o.) preparations encompass tablets and capsules, including syrups emulsions and suspensions to insure distribution throughout the gastrointestinal (GI) tract.
  • GI gastrointestinal
  • the invention also provides nanoparticles, nanolipoparticles, vesicles and liposomal membranes comprising compounds and compositions used to practice the methods of this invention.
  • the invention provides nanoparticles, nanolipoparticles, vesicles and liposomal membranes for low dosage and/or slow release of a compound of the invention.
  • the invention provides multilayered liposomes comprising compounds used to practice this invention, e.g., as described in Park, et al, U.S. Pat. Pub. No. 20070082042.
  • the multilayered liposomes can be prepared using a mixture of oil-phase components comprising squalane, sterols, ceramides, neutral lipids or oils, fatty acids and lecithins, to about 200 to 5000 nm in particle size, to entrap a composition used to practice this invention.
  • Liposomes can be made using any method, e.g., as described in Park, et al, U.S. Pat. Pub. No. 20070042031, including method of producing a liposome by encapsulating an active agent (e.g., a compound of the invention), the method comprising providing an aqueous solution in a first reservoir; providing an organic lipid solution in a second reservoir, and then mixing the aqueous solution with the organic lipid solution in a first mixing region to produce a liposome solution, where the organic lipid solution mixes with the aqueous solution to substantially instantaneously produce a liposome encapsulating the active agent; and immediately then mixing the liposome solution with a buffer solution to produce a diluted liposome solution.
  • an active agent e.g., a compound of the invention
  • liposome compositions used to practice this invention comprise a substituted ammonium and/or polyanions, e.g., for targeting delivery of a compound (e.g., e.g., a compound of the invention) used to practice this invention to a desired cell type or organ, e.g., brain, as described e.g., in U.S. Pat. Pub. No.
  • the invention also provides nanoparticles comprising compounds (e.g., a compound of the invention) used to practice this invention in the form of active agent- containing nanoparticles (e.g., a secondary nanoparticle), as described, e.g., in U.S. Pat. Pub. No. 20070077286.
  • the invention provides nanoparticles comprising a fat-soluble active agent of this invention or a fat-solubilized water-soluble active agent to act with a bivalent or trivalent metal salt.
  • solid lipid suspensions can be used to formulate and to deliver compositions used to practice this invention to mammalian cells in vivo, in vitro or ex vivo, as described, e.g., in U.S. Pat. Pub. No. 20050136121.
  • compositions and formulations of the invention can be administered for prophylactic and/or therapeutic treatments.
  • compositions or formulations of the invention are administered to a subject that is responsive to modulating, decreasing or increasing levels or activity of a dopamine in the CNS or brain, or is responsive to modulating, decreasing or increasing the activity of an nAChR in the CNS or brain (a "therapeutically effective amount").
  • the pharmaceutical compositions and formulations of the invention also can be administered as a preventative agent, e.g., prophylactically.
  • the amount of pharmaceutical composition adequate to accomplish this is defined as a "therapeutically effective dose.”
  • the dosage schedule and amounts effective for this use, i.e., the "dosing regimen,” will depend upon a variety of factors, including the stage of the exposure, the severity of the exposure, the general state of the patient's health, the patient's physical status, age and the like. In calculating the dosage regimen for a patient, the mode of administration also is taken into consideration.
  • the dosage regimen also takes into consideration pharmacokinetics parameters well known in the art, i.e., the active agents' rate of absorption, bioavailability, metabolism, clearance, and the like (see, e.g., Hidalgo-Aragones (1996) J. Steroid Biochem. Mol. Biol. 58:611-617; Groning (1996) Pharmazie 51 :337-341; Fotherby (1996) Contraception 54:59-69; Johnson (1995) J. Pharm. Sci. 84: 1144-1 146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24: 103-108; the latest Remington's, supra).
  • pharmacokinetics parameters well known in the art, i.e., the active agents' rate of absorption, bioavailability, metabolism, clearance, and the like (see, e.g., Hidalgo-Aragones (1996) J. Steroid Biochem. Mol. Biol. 58:
  • the invention also provides products of manufacture and kits for
  • the invention provides products of manufacture and kits comprising compounds, compositions and formulations of this invention, and comprising all the components needed to practice a method of the invention.
  • kits comprising compounds, compositions and formulations of this invention, and comprising compositions and/or instructions for practicing methods of the invention.
  • the invention provides kits comprising: a composition used to practice a method of any of the invention, optionally comprising instructions for use thereof.
  • the invention provides pumps, devices, subcutaneous infusion devices, continuous subcutaneous infusion device, infusion pens, needles, reservoirs, ampoules, vials, syringes, cartridges, disposable pen or jet injectors, prefilled pens or syringes or cartridges, cartridge or disposable pen or jet injectors, two chambered or multi-chambered pumps, syringes, cartridges or pens or jet injectors comprising a composition, composition or a formulation of the invention.
  • the injector is an auto injector, e.g., a SMART JECT® autoinjector (Janssen Research and Development LLC); or a MOLLY®, or DAI®, or DAI-RNS® autoinjector (SHL Group, Deerfield Beach, FL).
  • the injector is a hypodermic or a piston syringe.
  • Example 1 Exemplary compositions, formulations and combinations of the invention
  • This example describes exemplary compositions, formulations and combinations of the invention, and methods for making them.
  • the inventors used in situ click chemistry (see e.g., Kolb (2001)
  • nn ⁇ l the affinity for ligand at another site
  • the protein exhibits negative cooperativity, nn ⁇ l . It may also mean that two different independent binding sites with different affinities participate in ligand binding (see, e.g., KRIJSEK, Physiol. Res., 2004). Cooperative binding to AChBP can lead to ligands with unique pharmacological profiles.
  • nAChR agonists and antagonists To identify and characterize nAChR agonists and antagonists, we used cell4oased medium throughput fluorescence assays. One compound, KK-253B, passed the initial quick screen as a ⁇ 4 ⁇ 2 nAChR agonist and did not activate a7 nAChR. Additionally we found series of compounds that act as ⁇ 4 ⁇ 2 nAChR antagonists, as illustrated in Figure 3. For performing in situ click chemistry to identify potential dual-site binders, azides and alkynes were used as complementary reactants in triazole formation directed by the protein itself. Soluble forms of ⁇ 4 ⁇ 2 nAChR subtypes were used in these experiments. Ligands identified by mass spectrometry can be re-synthesized and tested to confirm activity.
  • Figure 7 schematically illustrates the crystal structure of Ls AChBP-ligand complex: Fig. 7(A) Side and Fig. 7(B) bottom side view showing molecules in five binding sites.
  • Figure 8 graphically illustrates representative titration profiles for 4,6-substituted
  • 2-aminopyrimidine (exemplary compounds of the invention, see Table 4, to associate numbering with structure) competition with 3 H-epibatidine binding showing a range of dissociation constants (3 ⁇ 4) and Hill coefficients (nn) for ligand binding to Zs-AChBP.
  • Figure 9 graphically illustrates global differences in X-ray crystal structures of Ls- AChBP bound cooperative ligands in comparison with crystal structure of Zs-AChBP in its Apo form.
  • Figure 14 summarizes data of X-ray crystal structures of exemplary compounds of the invention (ligands) 32 and 33 (negative cooperativity, n H ⁇ l) and exemplary compound 15 (positive cooperativity, n H >l), in complexes with Zs-AChBP:
  • Fig 9(A) illustrates radial view of Ls -AChBP pentameric structure in complex with exemplary compound of the invention 32;
  • Fig 9(B) illustrates an expanded radial view of exemplary compound 32 in binding site, including ligand electron density;
  • Fig. 9(C) illustrates overlay of exemplary compound 32 (blue) and exemplary compound 33
  • Fig 9(D) illustrates a superimposition of exemplary compound 15 (yellow) and exemplary compound 33 (blue) crystal structures.
  • Figure 17 schematically illustrates three (1, 2, 3) exemplary synthetic
  • Figure 18 schematically illustrates exemplary synthetic pathways of the invention to generate exemplary 2,4,5 -substituted pyrimidine compounds of the invention, including the so-called Formula I genus structure.
  • compositions including 4,6- disubstituted 2-aminopyrimidines, formulations and combinations of the
  • Both sets of molecules bind at the agonist-antagonist site, as expected from their competition with epibatidine (or, (lR,2R,45)-(+)-6-(6-chloro-3-pyridyl)-7-azabicyclo[2.2.1]heptane).
  • An analysis of AChBP quaternary structure shows that cooperative ligand binding is associated with a blooming or flare conformation, a structural change not observed with the classical, non- cooperative, nicotinic ligands.
  • Exemplary compounds of the invention behaved as positively and negatively cooperative ligands and exhibited unique features in the detailed binding determinants and poses of the complexes.
  • Nicotinic acetylcholine receptors function as allosteric pentamers of identical or homologous transmembrane spanning subunits. Ligand binding at two or more of the five inter-subunit sites, located radially in the extracellular domain, drives a conformational change that results in the opening of a centrosymmetric transmembrane channel, internally constructed amongst the five subunits (See Fig. l2A) (1-4). Up to five potential agonist-competitive antagonist sites on the pentamer are found at the outer perimeter of the subunit interfaces. Amino acid side chain determinants on both subunit interfaces dictate selectivity amongst the many subtypes of nAChRs.
  • nAChRs are hetero-oligomeric, where the sites of ligand occupation are not identical (1-4). This arrangement arises when a common a-subunit pairs with one or more non-identical subunit partners, termed non a-subunits (7-8). Non-identity of the subunit interface complementary to the a subunit may also give rise to heterogeneity in binding constants typically seen for antagonists and mask partially the degree of agonist cooperativity. An exception to this is the a7-neuronal nAChR composed of five identical subunits and exhibiting a high degree of cooperativity for agonist activation (9).
  • acetylcholine binding protein was characterized from mollusks (15-
  • AChBP exhibits a similar profile of ligand selectivity toward the classical nicotinic agonists and antagonists of quaternary amine, tertiary and secondary amine (alkaloid), imine, and peptide origin that bind nicotinic receptors (18-25). If looked at solely on the basis of ligand binding capacities, AChBP could be considered as a distinct subtype of nAChR.
  • Ligand 15 has a clear electron density for the bi-aryl ring of the molecule, but a poor density of the alkyl chain possibly arising from multiple flexible conformations of the C loop. Several residues in F the loop (T155-E163) gave unresolved electron densities and were consequently excluded from the models. Additionally, in complex with ligand 15, residues 185-189 in the C loop encompassing the vicinal Cys-Cys bond were not seen in nine often subunits of the dimer of pentamers.
  • Loop closure in the presence of bound ligands is 8.4 A for 32 and 33 structures and 8.2 A for 15.
  • the ligands contact amino acids from both the principal face with residues from loops A (Y89), B (W143), and C (Y185 and Y192), and complementary face (loops D: W53, E: LI 12 and Ml 14, F: Y164). Parallel displaced ⁇ -stacking interactions with W143 are present in all structures.
  • the ring rotation results in its parallel alignment with Y192 side chain (2.9 A and greater).
  • Morpholine (32) or 4-methyl-piperidine (33) substituents appear to associate with Y89 and Y185. Nitrogen atoms of these rings are positioned to stack with all 7 atoms of the Y185 ring with distances ranging between 3.6-4.3 A. Interactions of these substituents on the complementary subunit face are predominantly hydrophobic.
  • the altered position of the indole of W53 in 32 and 33, compared with 15, is associated with a change in side chain orientation of neighboring residues Ml 14 and Q55.
  • Phenyl rings substituted at the pyrimidine 6-position interact mainly with W143, Y192 and CI 88.
  • fluorines in trifluoromethyl substituent are in the vicinity of T 144 side chain and interact with multiple loop F residues, including LI 12 and Ml 14 as well as neighboring water molecules, with interaction extending to Ml 14 and R104 side chains.
  • the flexible aliphatic chain of 15 at the 4 position in the pyrimidine does not yield discernable electron densities except for chain D. This likely reflects multiple conformations of the flexible C loop not constrained by the symmetry related molecule in the crystal structure.
  • Rotation of the pyrimidine ring and presence of the alkyl chain in 15 brings the ligand in close contact with Y 185 side chain ( ⁇ 3.0 A to N4 of the ligand) and causes the tyrosine ring to rotate toward the gorge interface presumably to avoid a clash with the alkyl chain of the ligand.
  • the indole of W53 on the complementary face rotates towards the subunit interface and is in contact with ligand N4 (3.5 A).
  • the phenyl ring in ligand 15 has a similar position as the aromatic ring in complexes 32 or 33, but its contacts are altered by methoxy- substituent interacting with T144 and with LI 02, LI 12 and Ml 14 in the complementary face.
  • Major differences for 15, when compared to complexes of ligands showing negative cooperativity, are seen in Y185, Y164, Ml 14 and W53 side chains conformations.
  • the indole side chain in W53 changes its rotameric position.
  • Ml 14 is brought in contact with the 6- substituted trifluoromethyl phenyl group of the ligand.
  • the position of the 32/33 phenyl ring is similar to the pyridine ring in nicotine.
  • the trifluoromethyl group forces LI 12 to change its rotameric position.
  • Loop C in ligand 15 shows significant variation, reflected in the Y185 side chain conformation (Fig. 3B).
  • Residues W53 and Ml 14 in the 32/33 complexes, that represent most significant departures from nicotine, in the 15 X-ray structure have orientations similar to those in the nicotine complex.
  • the indole ring of W53 side chain has more extensive contacts with the ligand 15 than with nicotine, through its substituent at the position 4 in the pyrimidine ring.
  • the rotational state of Y164 on complementary face changes as well.
  • AChBP subunits accompanying ligand binding We report a series of selective AChBP ligands exhibiting negative as well as positive cooperativity, a type of allosteric behavior in which binding interactions in an oligomeric protein take place between distant subunit interfaces. Selected ligands showing marked differences in cooperativity were used to obtain three atomic resolution, X-ray crystal structures of ligands with different Hill slope values in their complexes with Zs-AChBP. The lower affinity ligands showing positive cooperativity, along with the high affinity of the negatively cooperative ligands, serve to achieve full occupation of ligand in the crystal structures.
  • the 2-aminopyrimidines may be considered as electron-rich ring systems capable of ring stacking with the side chains of Y192 and W143.
  • the pyrimidine ring nitrogens are not as exposed as the bicyclic ring in epibatidine and the pyrrolidine nitrogen in nicotine affording a proper directionality for hydrogen bonding.
  • the global conformational changes primarily manifested by blooming appear characteristic of the substituted 2-aminopyrimidines and are not seen with carbamylcholine and nicotine (Fig. 4 and Fig. S2). To date, a clear state change has only been documented for the substituted 2-aminopyrimidines.
  • AChBP quaternary structure add another dimension to considering subunit interactions.
  • the "blooming" and torsional conformational changes noted with AChBP show analogies with those observed in GLIC (13, 27) in relation with correspondences of protein sequence (Fig. 4, A, B & C and Fig. S2).
  • the amino terminal helix, regions between residues 58-70 and between 106-110 all show increased distances between diametrically opposed subunits.
  • the sharper negative peaks around residues 156 and 185 likely involve local perturbations of the C and F loops proximal to the ligand binding site resulting in local compaction of the structure, measured in Ca distances.
  • the comparison of the dihedral bond angles should reflect a torsional or twist motion as seen between the two states of GLIC (13, 27). Changes in dihedral angle positions are small (Fig. S2, C), but involve the same set of residues. Hence, when the binding of the 2- aminopyrimidines are compared with the pH dependent conformations of GLIC, the dominant common change is found with the Ca distances between diametric subunits (blooming) (Fig. S2 B), rather than the dihedral angles for torsional movement (twist) (Fig. S2 C).
  • interfacial binding sites residing under the C loop of AChBP and the nAChR appear surprisingly accommodating for the binding of ligands of different structure.
  • Stornaiaolo and colleagues have reported on large planar, aromatic molecules binding under the C loop in a stacked sandwich fashion, and extending the C loop (35).
  • benzodiazepines (36-37) and other sedative agents (38) that act in this manner with the GABA receptor (39-40). Accordingly, new dimensions for achieving pharmacologic selectivity for particular nAChR subtypes may result with the cooperative nAChR ligands possessing electron-rich substituted 2-aminopyrimidines.
  • Splitting patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), pentet (p), doublet of doublets (dd), doublet of doublet of doublets (ddd), doublet of triplets (dt), triplet of doublets (td) and broad (b); the value of chemical shifts ( ⁇ ) are given in ppm and coupling constants (J) in hertz (Hz).
  • Routine MS spectra were acquired in the positive ion mode using Agilent G2446ATM Lc/MSD Trap XCTTM coupled to an Agilent 1100TM HPLC.
  • Representative compounds were characterized by high-resolution mass spectrometry (HR-MS) by using an Agilent 6230 ESI-TOFMS. Analytical and preparative TLC was performed on aluminum-backed plates (EMD Chemicals, San Diego, CA) and visualized by exposure to UV light.
  • HR-MS high-resolution mass spectrometry
  • Scheme SI Synthetic pathway leading to 4,6-substituted 2-aminopyrimidines 1-38.
  • boronic acid (0.30 mmol) was added to a solution of appropriate chloropyrimidine (0.15 mmol) in N,N-dimethylacetamide (1.5 mL).
  • Potassium carbonate 2M (0.2mL) was added following the addition of 1 , 1 '-Bis(diplienylpliosphino)ferrocene- palladium(II)dichloridedichlorometha.ne complex (0.0112 mg, 0.015 mmol).
  • the resulting mixture was stirred in a capped glass vial at 140 °C for 2h. The solvents were removed under reduced pressure, brine was added and the mixture was extracted with ethyl acetate (3 x 20 mL).
  • CDCI 3 ⁇ 1.35 (m, 2 H), 1.41 (s, 9 H), 1.46 (m, 2 H), 1.57 (m, 2 H), 3.08 (m, 2 H), 3.28 (bs, 2 H), 5.09 (bs, 2 H), 6.13 (s, 1 H), 7.64 (m, 2 H), 7.96 (m, 2 H).
  • ESI- MS [Ci 9 H 2 4F 3 50 2 + H] + 412 (100). (m,
  • N 4 ,iV 4 -dibenzyl-6-(4-(trifluoromethyl) phenyl)pyrimidine-2,4-diamine AC-19-22).
  • 5-Bromo-2-chloro-4-(4-methylpiperidin-l- yl)pyrimidine AC-2-P: A solution 4- methylpiperidine (0.362 g, 3.65 mmol) and DIPEA (0.567 g, 4.38 mmol) in 10 ml THF was added dropwise to an ice-cold solution of 5-bromo-2,4-dichloropyrimidine (1.0 g, 4.38 mmol) in 10 ml dry THF. The solution was warmed up to room temperature and stirred overnight. Evaporation of the solvent provided with a crude product that was purified by
  • Figure 8 Representative titration profiles for 4,6-substituted 2-aminopyrimidine competition (using exemplary compounds of the invention 1, 15, 30 and 32, see Table 4, above) with 3 H-epibatidine binding showing a range of dissociation constants (3 ⁇ 4) and Hill coefficients (nn) for ligand binding to Zs-AChBP. Measurements were carried out by a scintillation proximity assay and are reported as an average of at least three individual experiments ( ⁇ S.D.).
  • Figure 9 shows X-ray crystal structures of exemplary compounds of the invention (ligands) 32 and 33 (negative cooperativity, n H ⁇ l) and 15 (positive cooperativity, n H >l), in complexes with Zs-AChBP (compound numbering corresponds to Table 4).
  • Fig 9(A) illustrates radial view of Zs-AChBP pentameric structure in complex with exemplary compound of the invention 32 (compound numbering corresponds to Table 4). Full occupation of the 10 binding sites in the unit crystal of a dimer of pentamers was evident. A principal, C loop containing, and complementary face are shown in grey and purple.
  • Fig 9(B) illustrates an expanded radial view of exemplary compound 32 in binding site, including ligand electron density.
  • Fig 9(C) illustrates an overlay of exemplary compound 32 (blue) and exemplary compound 33 (yellow) crystal structures. Side chain carbons for exemplary compound 32 are in turquoise. The overlay shows little or no variance in ligand pose or side chain positions.
  • exemplary compound 33 (yellow) and exemplary compound 33 (blue) crystal structures. Side chain carbons for exemplary compound 33 are in turquoise.
  • the positively exemplary compound 15 and negatively exemplary compounds 32/33 exemplary compounds of the invention are in turquoise.
  • Figure 10 shows the superimposition of Zs-AChBP X-ray crystal structures in complex with exemplary compound 33 (Fig. 10A) and exemplary compound 15 (Fig. 10B) with nicotine (PDB code: 1UW6, 18) (in orange).
  • exemplary compound 33 and exemplary compound 15 carbons are shown in yellow, nicotine in orange.
  • the protein side chains are shown in grey for exemplary compounds 33 and 15 and pink for nicotine.
  • Both ligands show distinctly different positions from the pyrrolidine and pyridine rings of nicotine, as well as the side chain positions of residues in the C loop in the principal subunit (Y89, Y185) and the complementary (W53 and Y164) subunit face.
  • Figure 11 shows the global differences in X-ray crystal structures of Zs-AChBP bound cooperative ligands in comparison with crystal structure of Zs-AChBP in its Apo form (PDB code: 1UX2) and GLIC (4NPP):
  • Fig. 1 1(A) schematically illustrates a top (apical) view on superimposed (UCSF chimera) Apo pentamer (in blue) and with bound exemplary compound 15 (in red), dashed lines (blue and red respectively) indicate most significant differences in quaternary structures quantified by measuring distances between T13 backbone alpha carbon of distant subunits;
  • Fig. 1 1(A) schematically illustrates a top (apical) view on superimposed (UCSF chimera) Apo pentamer (in blue) and with bound exemplary compound 15 (in red), dashed lines (blue and red respectively) indicate most significant differences in quaternary structures quantified by measuring distances between T13 backbone alpha carbon of distant subunits;
  • FIG. 1 1(B) schematically illustrates a superimposition (PyMOL) of Zs-AChBP Apo, chain D (in blue) and exemplary compound 15 complex, chain D (in red).
  • Major differences in the quaternary structures of the AChBP are marked with dashed rectangles (RMS value of approximately 0.5 or greater).
  • the Ls -AChBP was expressed and purified as previously reported (1, 2). Briefly,
  • AChBP was expressed with an amino-terminal FLAG epitope tag and secreted from stably transfected HEK293S cells lacking the N-acetylglucosaminyltransferase I (GnTI-) gene.
  • the protein was purified using FLAG-antibody resin and eluted with FLAG peptide (Sigma) and was further characterized by size-exclusion chromatography (SUPEROSE 6 10/300 GLTM column (GE Healthcare) in 50 mM Tris-HCl (pH 7.4), 150 mM NaCl,
  • AChBP pentamers were then concentrated in a YM50TM Centricon ultrafiltration unit (Millipore) removing monomeric subunits and trace contaminants. Protein concentrations were determined by UV absorbance at 280 nm (NANODROP (NanoDrop) 2000cTM spectrophotometer, ThermoScientific) and confirmed by Bradford assay.
  • NANODROP NanoDrop 2000cTM spectrophotometer
  • a scintillation proximity assay was employed to measure ligand binding to AChBP using [ 3 H]-epibatidine (5 nM, GE Healthcare) as the labeled ligand,
  • polyvinyltoluene anti-mouse SPA scintillation beads (0.17 mg/mL final concentration, GE Healthcare), monoclonal anti-FLAG M2 antibody from mouse 1 :8000 dilution
  • Ligand - Ls -AChBP complexes was formed by
  • Table 7 Data collection and refinement statistics.
  • Fig. 12(A) schematically illustrates an overlay of Zs-AChBP crystal structure in its Apo form (PDB code: 1UX2, shown in blue) and in complex with ligand 15 (in red), with GLIC X-ray crystal structure at pH 7.5 (PDB code: 4NPQ, shown in grey); X- ray structure of Zs-AChBP complex with nicotine and carbamylcholine (carbachol) used as controls (PDB codes: 1UW6 and 1UV6 respectively); stars represents position of the
  • Fig. 12(B) illustrates a chart representing 'bloom'; x axis: delta distance between C a observed in Zs-AChBP - ligand complexes when compared with Zs-AChBP Apo form (GLIC: X-ray structure obtained at pH 7.5 compared to the structure at pH 4); y axis: relative distance from the protein vestibule.
  • Fig. 12(C) illustrates a chart representing 'twist' of the pentameric structure; x axis: delta
  • reference points were defined by average coordinates of residue 194, average 5 coordinates of residue 12 and coordinates of residue 194 from corresponding subunit.
  • For GLIC reference points were defined by coordinates of residue 284 from corresponding subunit, average coordinates of residue 284 and average coordinates of residue 22.
  • Figure 14 Table 6, illustrated as Figure 14: shows competition between exemplary compounds of the invention (numbering corresponds to Table 4 compound
  • Figure 15 schematically illustrates an overlay of exemplary compound
  • Figure 16 illustrates a screening assay demonstrating activity of exemplary compounds of the invention (so-called compounds 17, KK-311-D and 171A, see
  • Fig. 16A and Fig. 16B compounds was screened at 50 uM and 10 uM, respectively, the nicotine agonist at 40 uM, and methyllycaconitine (or MLA) agonist at 400 uM; nicotine and MLA used a positive controls.
  • Compound 171 A (see Table 4) gave approximately 90% activation compared to nicotine.
  • Hibbs RE et al. (2009) Structural determinants for interaction of partial agonists with acetylcholine binding protein and neuronal alpha7 nicotinic acetylcholine receptor. £M5O J28(19):3040-3051.
  • Brams M, et al. (201 1) Crystal structures of a cysteine-modified mutant in loop D of acetylcholine-binding protein. J Biol Chem 286(6):4420-4428. Shahsavar A, et al. (2012) Crystal structure of Lymnaea stagnalis AChBP complexed with the potent nAChR antagonist ⁇ suggests a unique mode of antagonism. PLoS One 7(8):e40757.
  • Nicotine binding to brain receptors requires a strong cation-pi interaction.
  • Alpha-conotoxin OmIA is a potent ligand for the acetylcholine-binding protein as well as alpha3beta2 and alpha7 nicotinic acetylcholine receptors. J Biol Chem 281(34):24678-24686.
  • GABAA gamma-aminobutyric acid type-A

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Abstract

L'invention concerne des compositions et des procédés a) pour augmenter ou stimuler la libération d'autres transmetteurs (acides aminés excitateurs, acides aminés inhibiteurs et amines biogéniques) dans le système nerveux central (SNC) ou le cerveau, ou pour moduler, diminuer ou augmenter l'activité d'un AChR dans le SNC ou le cerveau, b) pour traiter, améliorer, prévenir ou diminuer les symptômes d'une dépendance ou d'une toxicomanie entraînant la modulation, la diminution ou l'augmentation des taux ou de l'activité de dopamine dans le SNC ou le cerveau, c) pour traiter, améliorer, prévenir ou diminuer les symptômes d'une dépendance ou d'une toxicomanie, comprenant par exemple des médicaments/drogues, des narcotiques ou du tabac, et d) pour traiter, améliorer, prévenir ou diminuer les symptômes d'une maladie ou d'un état, c'est-à-dire une démence, la maladie de Parkinson, la douleur ou la douleur chronique, l'allodynie, l'autisme, la psychose ou la schizophrénie, sensible à la modulation, ou à une diminution ou à une augmentation de l'activité de nAChR.
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US9975886B1 (en) 2017-01-23 2018-05-22 Cadent Therapeutics, Inc. Potassium channel modulators
CN110023331A (zh) * 2016-07-07 2019-07-16 霍华休斯医学研究院 经修饰的配体门控的离子通道及使用方法
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US10793551B2 (en) 2017-10-19 2020-10-06 Effector Therapeutics Inc. Benzimidazole-indole inhibitors of Mnk1 and Mnk2
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CN106950383A (zh) * 2017-03-23 2017-07-14 南京农业大学 蜘蛛乙酰胆碱结合蛋白在配体门控离子通道配体筛选中的用途
CN106950383B (zh) * 2017-03-23 2018-09-21 南京农业大学 蜘蛛乙酰胆碱结合蛋白在配体门控离子通道配体筛选中的用途
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US12247064B2 (en) 2017-11-10 2025-03-11 Howard Hughes Medical Institute Modified ligand-gated ion channels and methods of use
US11993586B2 (en) 2018-10-22 2024-05-28 Novartis Ag Crystalline forms of potassium channel modulators
WO2020210521A2 (fr) 2019-04-12 2020-10-15 The Regents Of The University Of California Compositions et procédés d'augmentation de la masse musculaire et du métabolisme oxydatif
EP3952849A4 (fr) * 2019-04-12 2023-03-01 The Regents Of The University Of California Compositions et procédés d'augmentation de la masse musculaire et du métabolisme oxydatif
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JP2025000907A (ja) * 2019-04-12 2025-01-07 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 筋肉量及び酸化的代謝を増加させるための組成物及び方法
JP2022526844A (ja) * 2019-04-12 2022-05-26 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 筋肉量及び酸化的代謝を増加させるための組成物及び方法
US12441716B2 (en) 2019-04-12 2025-10-14 The Regents Of The University Of California Compositions and methods for increasing muscle mass and oxidative metabolism
US11993580B1 (en) 2022-12-02 2024-05-28 Neumora Therapeutics, Inc. Methods of treating neurological disorders
US12371414B2 (en) 2022-12-02 2025-07-29 Neumora Therapeutics, Inc. Methods of treating neurological disorders

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