106 results about "GABAA receptor" patented technology

Compounds of Formula (1) are provided, as are methods for their preparation. The variables Z1, Z2, Z3, R4, R5, R6, R7, R8, and Ar in the above Formula are defined herein. Such compounds may be used to modulate ligand binding to GABAA receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of central nervous system (CNS) disorders in humans, domesticated companion animals, and livestock animals. Compounds provided herein may be administered alone or in combination with one or more other CNS agents to potentiate the effects of the other CNS agent(s). Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such ligands for detecting GABAA receptors (e.g., receptor localization studies).

Disclosed are compounds of the formula: and the pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein X, A, B, C, D and W are defined herein, which compounds bind with high selectivity and high affinity to the benzodiazepine site of the GABAA receptors and are therefore useful in the treatment of certain central nervous system (CNS) diseases and as probes for the localization of GABAA receptors in tissue samples.

Compositions for reducing dependency and addiction to substances of abuse are provided. Chloride channels such as the GABAA receptors are altered under conditions of dependency and withdrawal such that the electrophysiological properties of the GABAA receptor containing neurons are altered thereby providing a pathophysiological condition resulting in symptoms of dependency and withdrawal such as anxiety. Specifically, under conditions of withdrawal the relative ratio of the a1 receptor subunit decreases relative to the a4 receptor subunit. Endogenous neurosteroid production is also associated with the molecular changes underlying the alterations of GABA-gated chloride channels. Compositions of at least two compounds including at least one inhibitor of neurosteroid production are useful for treating the pathophysiology of addiction, dependency and substance abuse withdrawal.

Disclosed are compounds of the formula:and the pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein X, A, B, C, D and W are defined herein, which compounds bind with high selectivity and high affinity to the benzodiazepine site of the GABAA receptors and are therefore useful in the treatment of certain central nervous system (CNS) diseases and as probes for the localization of GABAA receptors in tissue samples.

The present invention is directed to the production of PKC isozyme epsi (PKCepsi)-deficient cells and non-human animals. The present invention is further directed to the identification of PKCepsi as a target for drugs that reduce anxiety. According to the present invention, PKCepsi-inhibiting compounds act in synergy with drugs acting at the GABAA receptor. The present invention is also directed to the use of modulators of PKCepsi to modulate alcohol consumption, self-administration of other drugs of abuse, and the effects of alcohol consumption as well as the use of inhibitors of PKCepsi, either alone or in conjunction with allosteric agonists of GABAA receptors, to treat conditions, such as addiction, withdrawal syndrome, skeletal muscle spasms, convulsive seizures, and epilepsy, that are amenable to treatment by allosteric agonists of GABAA receptors. Additional aspects of the present invention are diagnostic methods for identifying individuals at risk for becoming alcoholics or abusers of other drugs and kits for performing such diagnostic methods. The present invention relates to: cells and non-human animals deficient for the PKC isozyme epsi (PKCepsi); the use of PKCepsi as a target for drugs; the use of inhibitors of PKCepsi in methods of reducing anxiety and treating conditions associated with insufficient activity of the GABAA receptor; the use of modulators of PKCepsi in methods of modulating alcohol consumption, modulating self-administration of other drugs of abuse, and altering the effects of alcohol; pharmaceutical compositions comprising inhibitors of PKCepsi and allosteric agonists of GABAA receptors; and the identification of individuals with enhanced susceptibility to alcoholism or other forms of addiction.

Novel analogs and prodrugs of the loop diuretic bumetanide are described. Pharmaceutical compositions containing bumetanide analogs and prodrugs are also described. These analogs and prodrugs are particularly useful for the treatment and / or prophylaxis of conditions that involve the NKCC cotransporter family (NKCC1 and NKCC2), or the KCC cotransporter family (KCC1, KCC2, KCC3, KCC4), or GABAa receptors. Such conditions include, but are not limited to anxiety disorders, epilepsy, migraine, non-epileptic seizures, sleep disorders, obesity, eating disorders, autism, depression, edema, glaucoma, stroke, ischemia, neuropathic pain, addictive disorders, schizophrenia, psychosis, and tinnitus.

The invention is a process for producing haloalkyl pyrimidines as intermediates in the production of benzimidazole and / or pyridylimidazole derivatives having high selectivity and / or high affinity to the benzodiazepine site of GABAA receptors.

Provided herein are methods, drug formulations, and dosing regimens for improving cognitive function in a normal or cognitively impaired subject. For instance, methods provided herein comprise administering a GABAA receptor antagonist so that peak concentration of the GABAA receptor antagonist occurs when the subject is asleep.

The present invention relates to novel benzimidazole derivatives, pharmaceutical compositions containing these compounds, and methods of treatment therewith. The compounds of the invention are useful in the treatment of central nervous system diseases and disorders, which are responsive to modulation of the GABAA receptor complex, and in particular for inducing and maintaining anesthesia, sedation and muscle relaxation, as well as for combating febrile convulsions in children. The compounds of the invention may also be used by veterinarians.

The present invention relates to novel imidazo[1,2-a]pyridine compounds of general formula (I):as well as pharmaceutically acceptable salts thereof; wherein R1, R2, R3 and R4 are as defined in the claims. The compounds have specific affinity for GABAA receptor and are therefore useful in the treatment and prevention of diseases modulated by α1- and α2-GABAA receptors.

The invention provides compounds as shown in a general formula (I) which is described in the specification and cis-trans-isomers, enantiomers, diastereomers, racemes, solvates, hydrates, pharmaceutically acceptable salt and esters thereof. The invention further provides preparation method for the compounds, pharmaceutical compositions of the compounds and application of the compounds as modulators for an alpha5-GABAA receptor. T, Z, A and Y in the formula (I) are as defined in the specification.

The invention relates to a novel multi step process of making compounds of Formula I:wherein R1 is an alkoxy group and R2 is an optionally substituted, N-attached heteroaryl. The hydrogen at the 5-position can be α or β isomer, preferably α. Preferably the compound of Formula I is 17β isomer. The invention also relates to novel 3α-hydroxy-3β-substituted-17-substituted steroid compounds having GABAA receptor modulating activity, pharmaceutical compositions comprising these compounds, and the use of these compounds in a method of modulating brain excitability.

This invention relates to novel substituted benzimidazoles and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a compound that modulates the GABAA receptor. This invention also provides novel intermediates for the preparation of the compounds of the invention, and salts thereof.

Substituted imidazolylmethyl pyridine and pyrazine derivatives that bind to GABAA receptors are provided. Such compounds may be used to modulate ligand binding to GABAA receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of central nervous system (CNS) disorders in humans, domesticated companion animals and livestock animals. Compounds provided herein may be administered alone or in combination with one or more other CNS agents to potentiate the effects of the other CNS agent(s). Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such ligands for detecting GABAA receptors (e.g., receptor localization studies).

This invention relates to heteroaryl substituted fused bicyclic heteroaryl compounds, such as heteroaryl substituted imidazopyridines, imidazopyrazines, imidazopyridizines, imidazopyrimidines, and imidazothiazoles, which may be described by Formula I or Formula II: The invention is particularly related to such compounds that bind with high selectivity and high affinity to the benzodiazepine site of GABAA receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in treatment of certain central nervous system (CNS) diseases. Processes for preparing compounds of Formula I and Formula II are disclosed.This invention also relates to the use of benzimidazoles, pyridylimidazoles and related bicyclic heteroaryl compounds of Formula I or Formula II in combination with one or more other CNS agents to potentiate the effects of the other CNS agents. Additionally this invention relates to the use such compounds as probes for the localization of GABAA receptors in tissue sections.

The present invention provides methods for treating anxiety or irritability in a subject. The methods comprise administering to the subject an effective amount of an antagonist of allopregnanolone (THP), or a regulator which decreases expression of the alpha 4 subunit of GABA such as gabadoxbol (THIP), or a vector comprising an isolated nucleic acid molecule encoding a mutant alpha 4 subunit GABAA receptor protein having a neutral or non-basic amino acid residue substituted for the arginine residue at position 353 of the wild type mature protein, wherein this nucleic acid molecule is operably linked to a promoter which functions in the human brain. Such methods are useful in treating a subject undergoing a stage such as entering or having reached puberty, suffering from pre-menstrual syndrome (PMS), entering or having reached post-partem stage, entering or having reached menopause, and / or suffering from chronic stress. Also provided by the present isolated is a mutant alpha 4 subunit of GABAA receptor protein which has a neutral or non-basic amino acid residue substituted for the arginine residue at position 353 of the wild type mature protein and an isolated nucleic acid molecule encoding this mutated protein. The present invention also provides vectors comprising a subject isolated nucleic acid molecule operably liked to a promoter which functions in prokaryotic or eukaryotic cells, as well as host cells comprising such vectors. In addition, the present invention provides methods for identifying an antagonist of THP.

The invention relates to triazolopyridazine derivatives as well as a preparation method, a pharmaceutical composition and application thereof. The invention provides a compound shown in a general formula (I), cis-trans isomers, enantiomers, diastereoisomers, racemes, solvates, hydrates or pharmaceutically acceptable salts or prodrugs of the compound, and a preparation method of the compound, the cis-trans isomers, the enantiomers, the diastereoisomers, the racemes, the solvates, the hydrates or the pharmaceutically acceptable salts or the prodrugs of the compound; preparation method thereof; pharmaceutical compositions containing the compounds, and the use of the compounds as alpha 5-GABAA receptor modulators, wherein R 1, R 2, and Z are as defined in the specification. pharmaceutical compositions containing the compounds and application of the compounds as alpha-5-GABAA receptor modulators, wherein R1, R2 and Z are as defined in the specification.

The present invention relates to methods of and compositions for treating and relieving symptoms and disease associated with indications caused by a physiological drive to alleviate a sensation of anxiety. In one treatment method, methods of, and compositions for, modulating the expression of certain GABAA receptor subunits are used to treat anxiety-related disorders and depressive disorders associated with physiological tolerance to endogenous neurosteroids.

This invention relates to heteroaryl substituted fused bicyclic heteroaryl compounds, such as heteroaryl substituted imidazopyridines, imidazopyrazines, imidazopyridizines, imidazopyrimidines, and imidazothiazoles, which may be described by Formula I or Formula II: The invention is particularly related to such compounds that bind with high selectivity and high affinity to the benzodiazepine site of GABAA receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in treatment of certain central nervous system (CNS) diseases. Processes for preparing compounds of Formula I and Formula II are disclosed. This invention also relates to the use of benzimidazoles, pyridylimidazoles and related bicyclic heteroaryl compounds of Formula I or Formula II in combination with one or more other CNS agents to potentiate the effects of the other CNS agents. Additionally this invention relates to the use such compounds as probes for the localization of GABAA receptors in tissue sections.

This invention relates to cation conducting GABAA receptors, mutated GABAA receptor subunits, polynucleotide sequences encoding mutated subunits, expression vectors comprising the mutated subunits, host cells capable of expressing the mutated subunits, drug screening methods, and chemical substances identified by the drug screening methods of the invention.

Compounds of Formula I and Formula II are provided, as are methods for their preparation. The variables Y, Z1, Z2, Z3, R4, R5, R6, R7, R8 and Ar in the above formula are defined herein. Such compounds may be used to modulate ligand binding to GABAA receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of central nervous system (CNS) disorders in humans, domesticated companion animals and livestock animals. Compounds provided herein may be administered alone or in combination with one or more other CNS agents to potentiate the effects of the other CNS agent(s). Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such ligands for detecting GABAA receptors (e.g., receptor localization studies).

This invention relates to novel imidazole derivatives of the general formula (I): pharmaceutical compositions containing these compounds, and methods of treatment therewith. The compounds of the invention are useful in the treatment of central nervous system diseases and disorders, which are responsive to modulation of the GABAA receptor complex, and in particular for combating anxiety and related diseases.

The present invention relates to selective anxiolytic therapeutic agents which allow for the treatment of anxiety-related disorders with less severe side-effects, such as sedative and amnesic effects, and in particular, dependence liability. These selective agents selectively or preferentially bind the a2-GABAA receptor, as compared to the alpha1-GABAA receptor. Alternatively, these selective agents selectively or preferentially activate the alpha2-GABAA receptor, as compared to the alpha1-GABAA receptor. The present invention also relates to methods for identifying such selective anxiolytic therapeutic agents. The present invention also relates to methods for identifying a molecule that decreases binding of a benzodiazepine to the alpha1-GABAA receptor, but not substantially to the alpha2-GABAA receptor.

Substituted quinolone carboxylic acids and their derivatives are described. These compounds modulate the effect of γ-aminobutyric acid (GABA) via a novel site on the GABAA receptor complex in a therapeutically relevant fashion and may be used to ameliorate CNS disorders amenable to modulation of the GABAA receptor complex.

The present disclosure provides a pharmaceutical preparation of a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt, or prodrug thereof. The present disclosure further provides a method for general anesthesia or sedation for mammals. Also provided are kits and manufactured products of the medicament and the pharmaceutical composition and a method for using the medicament and the pharmaceutical composition.

Disclosed are 1H-Pyrrolo[3,2-b]pyridine-3-carboxylic acid amides that bind to the benzodiazepine site of GABAA receptors. Such compounds can be used to modulate ligand binding to GABAA receptors in vivo and in vitro, and are particularly useful in the treatment of a variety of central nervous system (CNS) disorders in humans, domesticated companion animals, and livestock animals.

This invention relates to novel imidazole derivatives, pharmaceutical compositions containing these compounds, and methods of treatment therewith.The compounds of the invention are useful in the treatment of central nervous system diseases and disorders, which are responsive to modulation of the GABAA receptor complex, and in particular for combating anxiety and related diseases.