Materials and methods for treatment of neurological disorders involving overactivation of glutamatergic ionotropic receptors

Abstract

The subject invention pertains to pharmaceutical compositions, articles of manufacture, and methods useful for treatment of neurological conditions related to, or which can be affected by, modulation of glutamate receptor (GluR) activity. The treatment can be either prophylactic in nature or to alleviate symptoms of such neurological conditions. The pharmaceutical compositions of the subject invention include an aromatic amino acid (AAA), an analog or isomer of an AAA, or combinations thereof, and pharmaceutically acceptable carrier or diluent. Methods of the subject invention involve parenterally administering to a patient at least one AAA, an analog or isomer of an AAA, or combination thereof.

We claim:  
     
         1 . A method for treating a neurological condition characterized by excessive activation of glutamatergic ionotropic receptors comprising parenterally administering at least one aromatic amino acid, isomer, or analog thereof, to a patient in need of such treatment.  
     
     
         2 . A method for treating a neurological condition characterized by excessive activation of glutomatergic ionotropic receptors comprising parenterally administering at least one aromatic amino acid, isomer, or analog thereof, to a patient in need of such treatment, wherein the neurological condition is not Parkinson's disease.  
     
     
         3 . The method, according to  claim 2 , wherein the neurological condition is selected from the group consisting of anoxic damage, hypoxic damage, traumatic brain injury, spinal cord injury, local anesthetic-induced seizure activity, ischemic stroke, ischemic neurodegeneration of the retina, epilepticus, Tourette's syndrome, obsessive-compulsive disorder, drug-induced CNS injury, chronic pain syndromes, lateral sclerosis, Alzheimer's disease, Huntington's chorea, AIDS dementia syndrome, and cocaine addiction, or combinations thereof.  
     
     
         4 . The method, according to  claim 2 , wherein the neurological condition is not a condition selected from the group consisting of multi-infarct dementia, Alzheimer's disease, and cocaine addiction.  
     
     
         5 . The method, according to  claim 2 , wherein the neurological condition is selected from the group consisting of ischemia, stroke, traumatic brain injury, hypoglycemia, and epileptic seizures.  
     
     
         6 . The method, according to  claim 2 , wherein the isomer is not D-phenylalanine.  
     
     
         7 . The method, according to  claim 2 , wherein the patient is suffering from the neurological condition.  
     
     
         8 . The method, according to  claim 2 , wherein the aromatic amino acid, isomer, or analog thereof, is administered to the patient intravenously.  
     
     
         9 . The method, according to  claim 2 , wherein the aromatic amino acid, isomer, or analog thereof, is administered to the patient intra-nasally.  
     
     
         10 . The method, according to  claim 2 , wherein the aromatic amino acid, isomer, or analog thereof, is administered in an amount sufficient to raise the concentration of the aromatic amino acid, isomer, or analog to above a physiologically normal level.  
     
     
         11 . The method, according to  claim 2 , wherein the aromatic amino acid, isomer, or analog thereof, is administered in an amount sufficient to raise the patient's blood plasma level of the aromatic amino acid, isomer, or analog, to within a range of about 200 μM to about 2000 μM.  
     
     
         12 . The method, according to  claim 2 , wherein the aromatic amino acid, isomer, or analog thereof, is administered in an amount sufficient to raise the patient's blood plasma level of the aromatic amino acid, isomer, or analog, to within a range of about 300 μM to about 1800 μM.  
     
     
         13 . The method, according to  claim 2 , wherein the aromatic amino acid, isomer, or analog thereof, is administered in an amount sufficient to raise the patient's blood plasma level of the aromatic amino acid, isomer, or analog, to within a range of about 800 μM to about 1500 μM.  
     
     
         14 . The method, according to  claim 2 , wherein said aromatic amino acid is selected from the group consisting of L-tyrosine, L-tryptophan, and L-phenylalanine.  
     
     
         15 . The method, according to  claim 2 , wherein a mixture of said aromatic amino acids are administered, and wherein said mixture is selected from the group consisting of: L-tyrosine and L-tryptophan; L-tyrosine and L-phenylalanine; L-tryptophan and L-phenylalanine; and L-tyrosine, L-tryptophan, and L-phenylalanine.  
     
     
         16 . The method, according to  claim 2 , wherein said aromatic amino acid isomer is an enantiomer selected from the group consisting of D-tyrosine, D-tryptophan, and D-phenylalanine.  
     
     
         17 . The method, according to  claim 2 , wherein a mixture of said aromatic amino acid isomers are administered, and wherein said mixture is selected from the group consisting of: D-tyrosine and D-tryptophan; D-tyrosine and D-phenylalanine; D-tryptophan and D-phenylalanine; and D-tyrosine, D-tryptophan, and D-phenylalanine.  
     
     
         18 . The method, according to  claim 2 , wherein a mixture of said aromatic amino acid and said isomer is administered, wherein said mixture comprises a levorotatory aromatic amino acid and a dextrorotatory aromatic amino acid.  
     
     
         19 . The method, according to  claim 2 , wherein in a mixture of said aromatic amino acid and said isomer is administered, and said mixture comprises L-phenylalanine and D-phenylalanine.  
     
     
         20 . The method, according to  claim 2 , wherein said aromatic amino acid, isomer, or analog is co-administered with a facilitating substance that increases transport of said aromatic amino acid, isomer, or analog across the blood-brain barrier.  
     
     
         21 . The method, according to  claim 20 , wherein said facilitating substance is an allosteric enhancer.  
     
     
         22 . The method, according to  claim 2 , wherein the analog has the structure of formula I  
       
         
           
           
               
               
           
         
         wherein R 1  and R 2 , which may be the same or different, are each selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy; wherein R 3  is selected from the group consisting of H, O, alkyl, alkenyl, alkynyl, halogen, and alkoxy; wherein R 4  is selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy, but wherein R 4  is not present when R 3  is O; and wherein R 5  is selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy.  
       
     
     
         23 . The method, according to  claim 22 , wherein R 3  and R 4  together form a ring structure selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.  
     
     
         24 . The method, according to  claim 23 , wherein the ring structure is optionally benzofused at any available position.  
     
     
         25 . The method, according to  claim 2 , wherein the analog has the structure of formula II  
       
         
           
           
               
               
           
         
         wherein R 1  and R 2 , which may be the same or different, are each selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy; wherein R 3  is selected from the group consisting of H, O, alkyl, alkenyl, alkynyl, halogen, and alkoxy; wherein R 4  is selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy, but wherein R 4  is not present when R 3  is O; and wherein R 5  is selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy.  
       
     
     
         26 . The method, according to  claim 2 , wherein the analog has the structure of formula III  
       
         
           
           
               
               
           
         
         wherein R 1  and R 2 , which may be the same or different, are each selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy; wherein R 3  is selected from the group consisting of H, O, alkyl, alkenyl, alkynyl, halogen, and alkoxy; wherein R 4  is selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy, but wherein R 4  is not present when R 3  is O; and wherein R 5  is selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy.  
       
     
     
         27 . The method, according to  claim 26 , wherein R 3  and R 4  together form a ring structure selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.  
     
     
         28 . The method, according to  claim 27 , wherein the ring structure is optionally benzofused at any available position.  
     
     
         29 . The method, according to  claim 2 , wherein the analog is 3,5-diiodo-L-tyrosine or 3,5-dibromo-L-tyrosine.  
     
     
         30 . A method for modulating the activity of a glutamate receptor comprising contacting an aromatic amino acid, isomer, or analog thereof, with said receptor, wherein said aromatic amino acid, isomer, or analog thereof, modulates the activity of said receptor.  
     
     
         31 . The method, according to  claim 30 , wherein said aromatic amino acid, isomer, or analog thereof, stimulates the activity of said glutamate receptor.  
     
     
         32 . The method, according to  claim 30 , wherein said aromatic amino acid, isomer, or analog thereof, inhibits the activity of said glutamate receptor.  
     
     
         33 . The method, according to  claim 30 , wherein said glutamate receptor is an ionotropic glutamate receptor.  
     
     
         34 . The method, according to  claim 30 , wherein said glutamate receptor is an metabotropic glutamate receptor.  
     
     
         35 . The method, according to  claim 30 , wherein said aromatic amino acid, isomer, or analog thereof is contacted with said receptor in vitro.  
     
     
         36 . The method, according to  claim 30 , wherein said aromatic amino acid, isomer, or analog thereof is contacted with said receptor in vivo.  
     
     
         37 . The method, according to  claim 30 , wherein said aromatic amino acid is selected from the group consisting of L-tyrosine, L-tryptophan, and L-phenylalanine.  
     
     
         38 . The method, according to  claim 30 , wherein a mixture of said aromatic amino acid and said isomer is contacted with said receptor, and wherein said mixture comprises a levorotatory aromatic amino acid and a dextrorotatory aromatic amino acid.  
     
     
         39 . The method, according to  claim 30 , wherein the isomer is not D-phenylalanine.  
     
     
         40 . The method, according to  claim 30 , wherein the analog has the structure of formula I  
       
         
           
           
               
               
           
         
         wherein R 1  and R 2 , which may be the same or different, are each selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy; wherein R 3  is selected from the group consisting of H, O, alkyl, alkenyl, alkynyl, halogen, and alkoxy; wherein R 4  is selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy, but wherein R 4  is not present when R 3  is O; and wherein R 5  is selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy.  
       
     
     
         41 . The method, according to  claim 40 , wherein R 3  and R 4  together form a ring structure selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.  
     
     
         42 . The method, according to  claim 41 , wherein the ring structure is optionally benzofused at any available position.  
     
     
         43 . The method, according to  claim 30 , wherein the analog has the structure of formula II  
       
         
           
           
               
               
           
         
         wherein R 1  and R 2 , which may be the same or different, are each selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy; wherein R 3  is selected from the group consisting of H, O, alkyl, alkenyl, alkynyl, halogen, and alkoxy; wherein R 4  is selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy, but wherein R 4  is not present when R 3  is O; and wherein R 5  is selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy.  
       
     
     
         44 . The method, according to  claim 30 , wherein the analog has the structure of formula III  
       
         
           
           
               
               
           
         
         wherein R 1  and R 2 , which may be the same or different, are each selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy; wherein R 3  is selected from the group consisting of H, O, alkyl, alkenyl, alkynyl, halogen, and alkoxy; wherein R 4  is selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy, but wherein R 4  is not present when R 3  is O; and wherein R 5  is selected from the group consisting of H, alky, alkenyl, alkynyl, halogen, and alkoxy.  
       
     
     
         45 . The method, according to  claim 44 , wherein R 3  and R 4  together form a ring structure selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.  
     
     
         46 . The method, according to  claim 45 , wherein the ring structure is optionally benzofused at any available position.  
     
     
         47 . The method, according to  claim 30 , wherein the analog is 3,5-diiodo-L-tyrosine or 3,5-dibromo-L-tyrosine.  
     
     
         48 . A pharmaceutical composition useful in treating a neurological condition characterized by overactivation of an ionotropic glutamatergic receptor, said composition comprising an aromatic amino acid, isomer, or analog thereof, and a pharmaceutically acceptable carrier or diluent.  
     
     
         49 . The pharmaceutical composition of  claim 48 , wherein said pharmaceutical composition further comprises a facilitating substance that increases transport of said aromatic amino acid, isomer, or analog, across the blood-brain barrier.  
     
     
         50 . The pharmaceutical composition of  claim 47 , wherein said facilitating substance is an allosteric enhancer.  
     
     
         51 . The pharmaceutical composition of  claim 48 , wherein said aromatic amino acid is selected from the group consisting of L-tyrosine, L-tryptophan, and L-phenylalanine.  
     
     
         52 . The pharmaceutical composition of  claim 48 , wherein said pharmaceutical composition comprises a mixture of said aromatic amino acids selected from the group consisting of: L-tyrosine and L-tryptophan; L-tyrosine and L-phenylalanine; L-tryptophan and L-phenylalanine; and L-tyrosine, L-tryptophan, and L-phenylalanine.  
     
     
         53 . The pharmaceutical composition of  claim 48 , wherein said aromatic amino acid isomer is an enantiomer selected from the group consisting of D-tyrosine, D-tryptophan, and D-phenylalanine.  
     
     
         54 . The pharmaceutical composition of  claim 48 , wherein said pharmaceutical composition comprises a mixture of said aromatic amino acid isomers selected from the group consisting of: D-tyrosine and D-tryptophan; D-tyrosine and D-phenylalanine; D-tryptophan and D-phenylalanine; and D-tyrosine, D-tryptophan, and D-phenylalanine.  
     
     
         55 . The pharmaceutical composition of  claim 48 , wherein said pharmaceutical composition comprises a mixture of aromatic amino acids and enantiomers thereof consisting of a dextrorotatory amino acid and a levorotatory amino acid.  
     
     
         56 . The pharmaceutical composition of  claim 48 , wherein said aromatic amino acid is a mixture of L-phenylalanine and D-phenylalanine.  
     
     
         57 . The pharmaceutical composition of  claim 48 , wherein said isomer is not D-phenylalanine.  
     
     
         58 . The pharmaceutical composition of  claim 48 , wherein said analog has the structure of formula I  
       
         
           
           
               
               
           
         
         wherein R 1  and R 2 , which may be the same or different, are each selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy; wherein R 3  is selected from the group consisting of H, O, alkyl, alkenyl, alkynyl, halogen, and alkoxy; wherein R 4  is selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy, but wherein R 4  is not present when R 3  is O; and wherein R 5  is selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy.  
       
     
     
         59 . The pharmaceutical composition of  claim 58 , wherein R 3  and R 4  together form a ring structure selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.  
     
     
         60 . The pharmaceutical composition of  claim 59 , wherein said ring structure is optionally benzofused at any available position.  
     
     
         61 . The pharmaceutical composition of  claim 48 , wherein said analog has the structure of formula II  
       
         
           
           
               
               
           
         
         wherein R 1  and R 2 , which may be the same or different, are each selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy; wherein R 3  is selected from the group consisting of H, O, alkyl, alkenyl, alkynyl, halogen, and alkoxy; wherein R 4  is selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy, but wherein R 4  is not present when R 3  is O; and wherein R 5  is selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy.  
       
     
     
         62 . The pharmaceutical composition of  claim 48 , wherein the analog has the structure of formula III  
       
         
           
           
               
               
           
         
         wherein R 1  and R 2 , which may be the same or different, are each selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy; wherein R 3  is selected from the group consisting of H, O, alkyl, alkenyl, alkynyl, halogen, and alkoxy; wherein R 4  is selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy, but wherein R 4  is not present when R 3  is O; and wherein R 5  is selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, and alkoxy.  
       
     
     
         63 . The pharmaceutical composition of  claim 62 , wherein R 3  and R 4  together form a ring structure selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.  
     
     
         64 . The pharmaceutical composition of  claim 63 , wherein said ring structure is optionally benzofused at any available position.  
     
     
         65 . The pharmaceutical composition of  claim 48 , wherein said analog is 3,5-diido-L-tyrosine or 3,5-dibromo-L-tyrosine.  
     
     
         66 . An article of manufacture useful in treating a neurological condition characterized by overactivation of an ionotropic glutamatergic receptor, said article containing a pharmaceutical composition comprising an aromatic amino acid, isomer, or analog thereof, and a pharmaceutically acceptable carrier or diluent.  
     
     
         67 . The article of manufacture of  claim 66 , wherein said article is an intravenous bag.  
     
     
         68 . The article of manufacture of  claim 66 , wherein said article is selected from the group consisting of a syringe, a nasal applicator, and a microdialysis probe.  
     
     
         69 . The article of manufacture of  claim 66 , wherein said article further comprises printed materials disclosing instructions for the parenteral treatment of the neurological condition.  
     
     
         70 . The article of manufacture of  claim 66 , wherein the printed material is embossed or imprinted on the article of manufacture and indicates the amount or concentration of aromatic amino acid, isomer, or analog thereof, recommended doses for parenteral treatment of the neurological condition, or recommended weights of patients to be treated.