WO2000057862A2 - Use of gaba-b receptor ligands for the treatment of neurodegenerative diseases - Google Patents
Use of gaba-b receptor ligands for the treatment of neurodegenerative diseases Download PDFInfo
- Publication number
- WO2000057862A2 WO2000057862A2 PCT/EP2000/002605 EP0002605W WO0057862A2 WO 2000057862 A2 WO2000057862 A2 WO 2000057862A2 EP 0002605 W EP0002605 W EP 0002605W WO 0057862 A2 WO0057862 A2 WO 0057862A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- gaba
- receptors
- ligand
- treatment
- cns
- Prior art date
Links
- 239000003446 ligand Substances 0.000 title claims abstract description 26
- 230000004770 neurodegeneration Effects 0.000 title claims description 9
- 208000015122 neurodegenerative disease Diseases 0.000 title claims description 6
- 102000017934 GABA-B receptor Human genes 0.000 title 1
- 108060003377 GABA-B receptor Proteins 0.000 title 1
- 108010025020 Nerve Growth Factor Proteins 0.000 claims abstract description 39
- 102000007072 Nerve Growth Factors Human genes 0.000 claims abstract description 21
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 claims description 11
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 claims description 11
- 239000002464 receptor antagonist Substances 0.000 claims description 9
- 229940044551 receptor antagonist Drugs 0.000 claims description 9
- 208000024827 Alzheimer disease Diseases 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 108090000742 Neurotrophin 3 Proteins 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000000018 receptor agonist Substances 0.000 claims description 4
- 229940044601 receptor agonist Drugs 0.000 claims description 4
- 208000004454 Hyperalgesia Diseases 0.000 claims description 3
- 208000035154 Hyperesthesia Diseases 0.000 claims description 3
- 230000002920 convulsive effect Effects 0.000 claims description 3
- 230000006378 damage Effects 0.000 claims description 3
- 231100000318 excitotoxic Toxicity 0.000 claims description 3
- 230000003492 excitotoxic effect Effects 0.000 claims description 3
- 230000028993 immune response Effects 0.000 claims description 3
- 230000002757 inflammatory effect Effects 0.000 claims description 3
- 230000000302 ischemic effect Effects 0.000 claims description 3
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 3
- 201000000980 schizophrenia Diseases 0.000 claims description 3
- 230000001629 suppression Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 2
- 208000024714 major depressive disease Diseases 0.000 claims 2
- 210000003169 central nervous system Anatomy 0.000 abstract description 7
- 102000015336 Nerve Growth Factor Human genes 0.000 description 17
- 229940053128 nerve growth factor Drugs 0.000 description 16
- 102000005962 receptors Human genes 0.000 description 14
- 108020003175 receptors Proteins 0.000 description 14
- 229940077737 brain-derived neurotrophic factor Drugs 0.000 description 9
- 210000004556 brain Anatomy 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 108020004999 messenger RNA Proteins 0.000 description 5
- 102000004230 Neurotrophin 3 Human genes 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 229940032018 neurotrophin 3 Drugs 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 210000001320 hippocampus Anatomy 0.000 description 3
- 238000011002 quantification Methods 0.000 description 3
- 210000000278 spinal cord Anatomy 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 230000008499 blood brain barrier function Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- 230000001054 cortical effect Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- ONNMDRQRSGKZCN-UHFFFAOYSA-N 3-aminopropyl(butyl)phosphinic acid Chemical compound CCCCP(O)(=O)CCCN ONNMDRQRSGKZCN-UHFFFAOYSA-N 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 101100404651 Mus musculus Ngf gene Proteins 0.000 description 1
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 1
- 101710138657 Neurotoxin Proteins 0.000 description 1
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 1
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 208000010366 Postpoliomyelitis syndrome Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 238000011481 absorbance measurement Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 208000018300 basal ganglia disease Diseases 0.000 description 1
- 230000006736 behavioral deficit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 108091092328 cellular RNA Proteins 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 230000007278 cognition impairment Effects 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000001073 episodic memory Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000000185 intracerebroventricular administration Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- BCDIWLCKOCHCIH-UHFFFAOYSA-N methylphosphinic acid Chemical compound CP(O)=O BCDIWLCKOCHCIH-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 208000005264 motor neuron disease Diseases 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 230000003959 neuroinflammation Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000006576 neuronal survival Effects 0.000 description 1
- 239000002581 neurotoxin Substances 0.000 description 1
- 231100000618 neurotoxin Toxicity 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 210000004129 prosencephalon Anatomy 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 208000002320 spinal muscular atrophy Diseases 0.000 description 1
- 238000010972 statistical evaluation Methods 0.000 description 1
- 208000005809 status epilepticus Diseases 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001228 trophic effect Effects 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 230000001755 vocal effect Effects 0.000 description 1
- 239000013585 weight reducing agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
-
- 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
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- 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
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to a new pharmaceutical use of ligands to GABA B receptors.
- Such compounds include GAB A B receptor antagonists, GABA B receptor agonists, GABA B receptor partial antagonists, GABAB receptor partial agonists and allosteric modulators of GABA B receptors.
- the present invention relates to the use of ligands to GAB A B receptors for increasing neurotrophin levels in the central nervous system (CNS).
- neurotrophins are known to be involved in neuronal survival, the growth and differentiation of synaptic efficacy and plasticity (Lo, D.C., 1996, Neuron 15, 979-981; Lessmann V., 1998, Gen. Pharmac. 31, 667-674).
- animal studies have shown that neurotrophins can reduce or prevent age-related axotomy or neurotoxin-induced neuronal loss or reduced function in a variety of brain regions and nerve growth factor (NGF) significantly improves cognition in aged rats (Fernandez C. et al, 1995, Mol. Chem. Neuropathol. 24, 241-244).
- NGF nerve growth factor
- neurotrophic factors are limited by the fact that they do not cross the blood-brain barrier and are easily metabolised by peptidases when administered peripherally (Barinaga, M. 1994, Science 264, 772-774).
- invasive neurosurgical procedures i.c.v. delivery catheter
- BDNF brain-derived neurotrophic factor
- Systemic treatment with trophic factors also causes serious side effects (Barinaga, see above).
- GABA B receptor antagonists enhance expression of neurotrophin mRNA and protein levels in various brain regions. Moreover it has been found that GABA B receptor antagonists exert said activity with a remarkably long duration of action.
- GABA B antagonists are known for example from USP 5,051,524 or USP 5,332,729.
- Specific GABA B antagonists include for example 3- ⁇ l(S)-[3-(cyclohexylmethyl)hydroxyphosphinyl)- 2(S)-hydroxy-propylamino]ethyl ⁇ benzoic acid (hereinafter compound A), 3- ⁇ l(R)-[3- (cyclohexylmethyl)hydroxyphosphinyl-2(S)-hydroxy-propylamino]ethyl ⁇ benzoic acid (hereinafter compound B) and 3-aminopropyl-(n-butyl)-phosphinic acid, and their salts.
- compound A 3- ⁇ l(S)-[3-(cyclohexylmethyl)hydroxyphosphinyl)- 2(S)-hydroxy-propylamino]ethyl ⁇ benzoic acid
- compound B 3-aminopropyl-(n-butyl)-phosphinic
- GABA B agonists are known for example from USP 5,281,747.
- Specific GABA B agonists include for example ⁇ -(aminomethyl)-4-chlorobenze propanoic acid (hereinafter compound C) and 3-amino-2S-hydroxypropyl methylphosphinic acid.
- compound C ⁇ -(aminomethyl)-4-chlorobenze propanoic acid
- 3-amino-2S-hydroxypropyl methylphosphinic acid 3-amino-2S-hydroxypropyl methylphosphinic acid.
- Total cellular RNA is isolated according to the TRLZOL®-protocol (Gibco BRL, Eggenstein) as described by L ⁇ esse et al. (see above).
- RNA extracts are supplemented with internal control RNA and optimized as described in detail by Heese K. et al., 1998, Neural Notes III, 21-23.
- Total RNA of each sample is first reverse-transcribed into cDNA which in turn is subjected to PCR amplification using primers specific for NGF and BDNF as described by Heese K. et al., (see above).
- GAB A B receptor antagonists at doses of about 0.1 to about 600 mg/kg i.p. significantly increase NGF- and BDNF-mRNA in the cortex, hippocampus and spinal cord 6 to 24 hours after treatment and significantly increase NGF- and BDNF-protein levels in said regions 12 to 72 hours after treatment.
- GABA B receptor agonists at doses of about 0.1 to about 10 mg/kg i.p. significantly increase NT-3-protein levels in the cortex, hippocampus and spinal cord 24 to 96 hours after treatment.
- GABA B receptor antagonists are useful for the treatment of conditions responsive to an increase of NGF and BDNF
- GABA B receptor agonists are useful for the treatment of conditions responsive to an increase of NT-3.
- Such conditions include neurodegenerative diseases such as Alzheimer's and related diseases, and stress-induced neurodegeneration; motor neuron diseases, e.g.
- amyotrophic lateral sclerosis spinal muscular atrophy and post-polio syndrome
- Parkinson's disease and syndromes and suppression of immune responses following CNS tissue grafts
- Huntington's chorea and other basal ganglia disorders spinal cord injury and head trauma
- neuroinflammation e.g. multiple sclerosis, inflammatory hyperalgesia; severe depression states; schizophrenia; furthermore peripheral neuropathy; convulsive states, e.g. status epilepticus and excitotoxic/ischemic damages.
- the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.1 to about 600 mg/kg body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 1 to about 2000 mg of a compound for use according to the invention conveniently administered, for example, in divided doses up to five times a day.
- the present invention accordingly provides the use of a ligand to GABA B receptors in the treatment of the above-mentioned conditions.
- the ligand to GABA B receptors may be administered as single active agent or in combination with other active agents, in any usual manner, e.g. orally, for example in the form of tablets or capsules, or parenteraUy, for example in the form of injection solutions or suspensions.
- the present invention provides pharmaceutical compositions comprising the ligand to GABA B receptors in association with at least one pharmaceutical carrier or diluent for use in the treatment of any of the above-indicated diseases.
- Such compositions may be manufactured in conventional manner.
- Unit dosage forms may contain, for example, from about 0.25 to about 500 mg of the ligand to GABA B receptors.
- the present invention also provides the use of a ligand to GABA B receptors for the manufacture of a pharmaceutical composition for the treatment of any of the above-indicated diseases.
- the invention furthermore provides a method for increasing neurotrophin levels in the CNS, particularly for the treatment of any of the above-indicated diseases, in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of a ligand to GABA B receptors.
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Immunology (AREA)
- Urology & Nephrology (AREA)
- Anesthesiology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Hospice & Palliative Care (AREA)
- Heart & Thoracic Surgery (AREA)
- Psychology (AREA)
- Transplantation (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000607613A JP2002540143A (en) | 1999-03-25 | 2000-03-23 | Novel use of GABAB receptor ligand |
EP00914167A EP1143942B1 (en) | 1999-03-25 | 2000-03-23 | Use of gaba-b receptor ligands for the manufacture of medicaments for the treatment of neurodegenerative diseases |
AT00914167T ATE246922T1 (en) | 1999-03-25 | 2000-03-23 | USE OF GABA-B RECEPTOR LIGANDS FOR PRODUCING MEDICATIONS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES |
AU35579/00A AU3557900A (en) | 1999-03-25 | 2000-03-23 | New use of ligands to gabab receptors |
DE60004473T DE60004473T2 (en) | 1999-03-25 | 2000-03-23 | USE OF GABA-B RECEPTOR LIGANDS FOR THE PRODUCTION OF MEDICATIONS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES |
US09/955,381 US20020013257A1 (en) | 1999-03-25 | 2001-09-18 | Use of ligands to GABAB receptors |
US11/365,437 US20060148707A1 (en) | 1999-03-25 | 2006-03-01 | Use of ligands to GABA beta receptors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9906882.7A GB9906882D0 (en) | 1999-03-25 | 1999-03-25 | Organic compounds |
GB9906882.7 | 1999-03-25 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/955,381 Continuation US20020013257A1 (en) | 1999-03-25 | 2001-09-18 | Use of ligands to GABAB receptors |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2000057862A2 true WO2000057862A2 (en) | 2000-10-05 |
WO2000057862A3 WO2000057862A3 (en) | 2001-08-09 |
Family
ID=10850330
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2000/002605 WO2000057862A2 (en) | 1999-03-25 | 2000-03-23 | Use of gaba-b receptor ligands for the treatment of neurodegenerative diseases |
Country Status (10)
Country | Link |
---|---|
US (2) | US20020013257A1 (en) |
EP (1) | EP1143942B1 (en) |
JP (1) | JP2002540143A (en) |
AT (1) | ATE246922T1 (en) |
AU (1) | AU3557900A (en) |
DE (1) | DE60004473T2 (en) |
ES (1) | ES2204542T3 (en) |
GB (1) | GB9906882D0 (en) |
PT (1) | PT1143942E (en) |
WO (1) | WO2000057862A2 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002074293A2 (en) * | 2001-03-15 | 2002-09-26 | Saegis Pharmaceuticals Inc | Methods for restoring cognitive function following systemic stress |
WO2008033572A1 (en) * | 2006-09-15 | 2008-03-20 | Xenoport, Inc. | Acyloxyalkyl carbamate prodrugs, methods of synthesis and use |
US7494985B2 (en) | 2004-11-03 | 2009-02-24 | Xenoport, Inc. | Acyloxyalkyl carbamate prodrugs, methods of synthesis, and use |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005112908A1 (en) * | 2004-05-14 | 2005-12-01 | The Johns Hopkins University | Method for improving cognitive function |
JP2012158527A (en) * | 2011-01-31 | 2012-08-23 | Mitsubishi Gas Chemical Co Inc | Prophylaxis of depression |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3978216A (en) * | 1974-06-03 | 1976-08-31 | Nelson Research & Development Company | Method for treating schizophrenia and method and composition for potentiating neuroleptic drugs |
EP0319479A2 (en) * | 1987-12-04 | 1989-06-07 | Ciba-Geigy Ag | Substituted propane-phosphinic acid compounds |
EP0399949A1 (en) * | 1989-05-13 | 1990-11-28 | Ciba-Geigy Ag | Substituted aminoalkylphosphinic acids |
EP0463969A1 (en) * | 1990-06-27 | 1992-01-02 | Adir Et Compagnie | New compounds of 4-aminobutyric acid, process for their preparation and pharmaceutical preparations containing them |
EP0569333A2 (en) * | 1992-05-08 | 1993-11-10 | Ciba-Geigy Ag | Novel N-aralkyl and N-heteroaralkylamino alcane phosphinic acids |
FR2722192A1 (en) * | 1994-07-06 | 1996-01-12 | Adir | New optically active 3-substd. 4-amino:butyric acid derivs. |
WO1997046675A1 (en) * | 1996-05-30 | 1997-12-11 | Novartis Ag | Metabotropic gaba[b] receptors, receptor-specific ligands and their uses |
WO1998028313A1 (en) * | 1996-12-24 | 1998-07-02 | Novartis Ag | (thio)morpholine-substituted carboxylic and phosphinic acids |
WO1998058939A1 (en) * | 1997-06-23 | 1998-12-30 | Polychip Pharmaceuticals Pty. Ltd. | Neurologically-active compounds |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5214063A (en) * | 1990-06-27 | 1993-05-25 | Adir Et Compagnie | 4-aminobutyric acid compounds, compositions and methods of use for treating disorders related to a dysfunction of GABAB receptors |
US6113947A (en) * | 1997-06-13 | 2000-09-05 | Genentech, Inc. | Controlled release microencapsulated NGF formulation |
-
1999
- 1999-03-25 GB GBGB9906882.7A patent/GB9906882D0/en active Pending
-
2000
- 2000-03-23 WO PCT/EP2000/002605 patent/WO2000057862A2/en active IP Right Grant
- 2000-03-23 ES ES00914167T patent/ES2204542T3/en not_active Expired - Lifetime
- 2000-03-23 PT PT00914167T patent/PT1143942E/en unknown
- 2000-03-23 DE DE60004473T patent/DE60004473T2/en not_active Expired - Fee Related
- 2000-03-23 EP EP00914167A patent/EP1143942B1/en not_active Expired - Lifetime
- 2000-03-23 AU AU35579/00A patent/AU3557900A/en not_active Abandoned
- 2000-03-23 JP JP2000607613A patent/JP2002540143A/en active Pending
- 2000-03-23 AT AT00914167T patent/ATE246922T1/en not_active IP Right Cessation
-
2001
- 2001-09-18 US US09/955,381 patent/US20020013257A1/en not_active Abandoned
-
2006
- 2006-03-01 US US11/365,437 patent/US20060148707A1/en not_active Abandoned
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3978216A (en) * | 1974-06-03 | 1976-08-31 | Nelson Research & Development Company | Method for treating schizophrenia and method and composition for potentiating neuroleptic drugs |
EP0319479A2 (en) * | 1987-12-04 | 1989-06-07 | Ciba-Geigy Ag | Substituted propane-phosphinic acid compounds |
EP0399949A1 (en) * | 1989-05-13 | 1990-11-28 | Ciba-Geigy Ag | Substituted aminoalkylphosphinic acids |
EP0463969A1 (en) * | 1990-06-27 | 1992-01-02 | Adir Et Compagnie | New compounds of 4-aminobutyric acid, process for their preparation and pharmaceutical preparations containing them |
EP0569333A2 (en) * | 1992-05-08 | 1993-11-10 | Ciba-Geigy Ag | Novel N-aralkyl and N-heteroaralkylamino alcane phosphinic acids |
FR2722192A1 (en) * | 1994-07-06 | 1996-01-12 | Adir | New optically active 3-substd. 4-amino:butyric acid derivs. |
WO1997046675A1 (en) * | 1996-05-30 | 1997-12-11 | Novartis Ag | Metabotropic gaba[b] receptors, receptor-specific ligands and their uses |
WO1998028313A1 (en) * | 1996-12-24 | 1998-07-02 | Novartis Ag | (thio)morpholine-substituted carboxylic and phosphinic acids |
WO1998058939A1 (en) * | 1997-06-23 | 1998-12-30 | Polychip Pharmaceuticals Pty. Ltd. | Neurologically-active compounds |
Non-Patent Citations (11)
Title |
---|
"GABA B RECEPTOR ANTAGONISTS: FROM SYNTHESIS TO THERAPEUTIC APPLICATIONS" TRENDS IN PHARMACOLOGICAL SCIENCES,ELSEVIER TRENDS JOURNAL, CAMBRIDGE,GB, vol. 14, 1993, pages 391-393, XP000946102 ISSN: 0165-6147 cited in the application * |
ENNA, S. J. ET AL: "Regulation of neurokinin-1 receptor expression by GABAB receptor agonists" LIFE SCI. (1998), 62(17/18), 1525-1530 , XP000983025 * |
GEORGE, B. ET AL: "Protective effects of GABAergic drugs and other anticonvulsants in lithium-pilocarpine-induced status epilepticus." METHODS AND FINDINGS IN EXPERIMENTAL AND CLINICAL PHARMACOLOGY, (1996) VOL. 18, NO. 5, PP. 335-340. , XP000981822 * |
HEESE K ET AL: "GABA B RECEPTOR ANTAGONISTS ELEVATE BOTH MRNA AND PROTEIN LEVELS OFTHE NEUROTROPHINS NERVE GROWTH FACTOR (NGF) AND BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) BUT NOT NEUROTROPHIN-3 (NT-3) IN BRAIN AND SPINAL CORD OF RATS" NEUROPHARMACOLOGY,PERGAMON PRESS, OXFORD,GB, vol. 39, 2000, pages 449-462, XP000938344 ISSN: 0028-3908 * |
J.E.F. REYNOLDS: "MARTINDALE, The Extra Pharmacopoeia" 1996 , ROYAL PHARMACEUTICAL SOCIETY , LONDON XP002160961 page 1515 -page 1516 Baclofen * |
KULINSKII, V. I. ET AL: "Effect of bilateral destruction of the subretrofacial area on receptor mechanisms of neuroprotective effect of GABAergic agents" BULL. EXP. BIOL. MED. (1998), 125(2), 139-141 , XP000981867 * |
LAL, SUMEER ET AL: "Baclofen is cytoprotective to cerebral ischemia in gerbils" NEUROCHEM. RES. (1995), 20(2), 115-19 , XP000981832 * |
LEES A J ET AL: "BACLOFEN IN PARKINSONS DISEASE." J NEUROL NEUROSURG PSYCHIATRY, (1978) 41 (8), 707-708. , XP000981829 * |
POTASHNER, S. J. ET AL: "Kainate-enhanced release of D-[3HÜaspartate from cerebral cortex and striatum: reversal by baclofen and pentobarbital" J. NEUROCHEM. (1983), 40(6), 1548-57 , XP000981821 * |
SMITH, G. D. (1) ET AL: "Increased sensitivity to the antinociceptive activity of (racemic)-baclofen in an animal model of chronic neuropathic, but not chronic inflammatory hyperalgesia." NEUROPHARMACOLOGY, (1994) VOL. 33, NO. 9, PP. 1103-1108. , XP000986543 * |
YU, ZAIFANG (1) ET AL: "Mechanism of colchicine impairment on learning and memory, and protective effect of CGP-36742 in mice." BRAIN RESEARCH, (1997) VOL. 750, NO. 1-2, PP. 53-58. , XP000981780 * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002074293A2 (en) * | 2001-03-15 | 2002-09-26 | Saegis Pharmaceuticals Inc | Methods for restoring cognitive function following systemic stress |
WO2002074293A3 (en) * | 2001-03-15 | 2003-08-28 | David Pharmaceuticals | Methods for restoring cognitive function following systemic stress |
US7494985B2 (en) | 2004-11-03 | 2009-02-24 | Xenoport, Inc. | Acyloxyalkyl carbamate prodrugs, methods of synthesis, and use |
US7935686B2 (en) | 2004-11-03 | 2011-05-03 | Xenoport, Inc. | Acyloxyalkyl carbamate prodrugs, methods of synthesis, and use |
WO2008033572A1 (en) * | 2006-09-15 | 2008-03-20 | Xenoport, Inc. | Acyloxyalkyl carbamate prodrugs, methods of synthesis and use |
US7585996B2 (en) | 2006-09-15 | 2009-09-08 | Xenoport, Inc. | Acyloxyalkyl carbamate prodrugs, methods of synthesis and use |
US7749985B2 (en) | 2006-09-15 | 2010-07-06 | Xenoport, Inc. | Acyloxyalkyl carbamate prodrugs, methods of synthesis and use |
Also Published As
Publication number | Publication date |
---|---|
JP2002540143A (en) | 2002-11-26 |
ES2204542T3 (en) | 2004-05-01 |
WO2000057862A3 (en) | 2001-08-09 |
EP1143942A2 (en) | 2001-10-17 |
GB9906882D0 (en) | 1999-05-19 |
AU3557900A (en) | 2000-10-16 |
DE60004473T2 (en) | 2004-07-08 |
EP1143942A3 (en) | 2002-09-11 |
US20020013257A1 (en) | 2002-01-31 |
US20060148707A1 (en) | 2006-07-06 |
DE60004473D1 (en) | 2003-09-18 |
EP1143942B1 (en) | 2003-08-13 |
PT1143942E (en) | 2003-12-31 |
ATE246922T1 (en) | 2003-08-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10441558B2 (en) | Therapeutic approaches for treating CMT and related disorders | |
Heese et al. | GABAB receptor antagonists elevate both mRNA and protein levels of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) but not neurotrophin-3 (NT-3) in brain and spinal cord of rats | |
Pertovaara et al. | Pharmacological properties, central nervous system effects, and potential therapeutic applications of atipamezole, a selective α2‐adrenoceptor antagonist | |
EP3368080B1 (en) | Treatment of nervous system disorders using combinations of rxr agonists and thyroid hormones | |
EP3368160B1 (en) | Treatment of nervous system disorders using thyroid hormone neutral doses of rxr agonists | |
US20060148707A1 (en) | Use of ligands to GABA beta receptors | |
US5622981A (en) | Use of metabotropic receptor agonists in progressive neurodegenerative diseases | |
JP2000514420A (en) | Use of K-252A Derivatives for the Treatment of Peripheral or Central Nervous Disorders and Cytokine Overproduction | |
Li et al. | Targeting mGluR2/3 for treatment of neurodegenerative and neuropsychiatric diseases | |
US6043251A (en) | Use of 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyr idine for preparing drugs for treating amyotrophic lateral sclerosis | |
WO1999053956A1 (en) | Remedies for obesity | |
US10695437B2 (en) | Polycomplexes of poly-lysine compounds for preventing and/or combatting amyotrophic lateral sclerosis | |
Piekarz et al. | Pharmacologic treatment with OKN-007 reduces alpha-motor neuron loss in spinal cord of aging mice | |
WO2013070011A1 (en) | Pharmaceutical composition for the prevention or treatment of neurological diseases comprising an ampa receptor endocytosis inhibitor | |
WO2022178423A1 (en) | Okn-007 as an agent to improve longevity | |
AU2016256808B2 (en) | New therapeutic approaches for treating CMT and related disorders | |
WO2004105756A2 (en) | Combination comprising (a) a neuroprotecting agent and (b) an agent binding to gadph and pharmaceutical use thereof | |
WO2022094565A1 (en) | N-propargylglycine: a unique inhibitor of proline dehydrogenase with brain-enhancing mitohormesis properties capable of mitigating neurodegenerative disorders | |
CN117338938A (en) | Combination therapy for the treatment of central nervous system disorders |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2000914167 Country of ref document: EP |
|
AK | Designated states |
Kind code of ref document: A3 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
WWE | Wipo information: entry into national phase |
Ref document number: 09955381 Country of ref document: US |
|
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 2000 607613 Kind code of ref document: A Format of ref document f/p: F |
|
WWP | Wipo information: published in national office |
Ref document number: 2000914167 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWG | Wipo information: grant in national office |
Ref document number: 2000914167 Country of ref document: EP |