Methods for Dopamine Modulation in Human Neurologic Diseases

Abstract

A method of treating Parkinson's Disease, Huntington's Disease and the like, diseases with abnormal dopamine-neurotransmission, using small molecules administered systemically that penetrate into the central nervous system to inhibit the rate-limiting step of dopamine synthesis in the central nervous system, the conversion of L-tyrosine to L-3, 4-dihydroxyphenylalanine (L-DOPA) by tyrosine hydroxylase along with its cofactors tetrahydrobiopterin and iron (Fe+).

What is claimed is: 
     
         1 . A method of treating neurodegenerative diseases and disorders by administering a composition for antagonizing tyrosine hydroxylase. 
     
     
         2 . The method of  claim 1 , wherein the neurodegenerative condition is Parkinson's disease. 
     
     
         3 . The method of  claim 2 , wherein the neurodegenerative condition is Parkinsonism. 
     
     
         4 . The method of  claim 1 , wherein the neurodegenerative condition is Huntington's disease. 
     
     
         5 . The method of  claim 3 , wherein the cause of Parkinsonism is progressive supranuclear palsy. 
     
     
         6 . The method of  claim 3 , wherein the cause of Parkinsonism is multiple system atrophy. 
     
     
         7 . The method of  claim 3 , wherein the cause of Parkinsonism is diffuse Lewy Body disease. 
     
     
         8 . The method of  claim 3 , wherein the cause of Parkinsonism is drug-induced Parkinsonism. 
     
     
         9 . The method of  claim 3 , wherein the cause of Parkinsonism is Creutzfeldt-Jakob disease. 
     
     
         10 . The method of  claim 3 , wherein the cause of Parkinsonism is due to chronic brain trauma. 
     
     
         11 . The method of  claim 3 , wherein the cause of Parkinsonism is linked to a genetic abnormality. 
     
     
         12 . The method of  claim 3 , wherein the genetic cause is GBA, LRRK2, SNCA, VPS35, Parkin, PINK1 and/or DJ1. 
     
     
         13 . The method of  claim 4 , wherein the Huntington's patient manifests choreiform and/or bradykinetic state(s). 
     
     
         14 . The method of  claim 1 , wherein tyrosine hydroxylase activity is inhibited by a direct biochemical effect on that enzyme. 
     
     
         15 . The method of  claim 1 , wherein tyrosine hydroxylase activity is inhibited by an indirect biochemical effect on that enzyme through inhibition of the biosynthesis of its cofactor tetrahydrobiopterin. 
     
     
         16 . The method of  claim 1 , wherein tyrosine hydroxylase activity is inhibited by co-administration of a direct inhibitor of that enzyme and indirectly through an antagonist of the biosynthesis of that enzyme's cofactor, tetrahydrobiopterin. 
     
     
         17 . The method of  claim 14 , wherein the tyrosine hydroxylase inhibitor is alpha-methyl-p-tyrosine. 
     
     
         18 . The method of  claim 17 , wherein alpha-methyl-p-tyrosine is administered at a dose ranging from initial administration at a range of 1 mg daily up to 250 mg daily with the target maintenance dose at a range from 100 mg daily to 1000 grams daily. 
     
     
         19 . The method of  claim 17 , wherein alpha-methyl-p-tyrosine is administered intra-nasally. 
     
     
         20 . The method of  claim 19 , wherein intra-nasal alpha-methyl-p-tyrosine is administered at doses 1/10 to 1/100 of oral doses listed in 15. 
     
     
         21 . The method of  claim 17 , wherein alpha-methyl-p-tyrosine is administered in the salt, ester, tartrate, gluconate, carbonate, anhydrous or free base forms. 
     
     
         22 . The method of  claim 17 , wherein alpha-methyl-p-tyrosine is administered in conjunction with levodopa, levodopa analog or dopaminergic containing medicines. 
     
     
         23 . The method of  claim 22 , wherein the levodopa, levodopa analog or dopaminergic containing medication doses are adjusted during the initiation and ongoing administration of alpha-methyl-p-tyrosine as clinically indicated. 
     
     
         24 . The method of  claim 17 , wherein alpha-methyl-p-tyrosine is administered in conjunction with MAO-B inhibitors. 
     
     
         25 . The method of  claim 24 , wherein the MAO-B inhibitors doses are adjusted during the initiation and ongoing administration of alpha-methyl-p-tyrosine as clinically indicated. 
     
     
         26 . The method of  claim 17 , wherein alpha-methyl-p-tyrosine is administered in conjunction with COMT inhibitors. 
     
     
         27 . The method of  claim 26 , wherein the COMT-inhibitors doses are adjusted during the initiation and ongoing administration of alpha-methyl-p-tyrosine as clinically indicated. 
     
     
         28 . The method of  claim 17 , wherein alpha-methyl-p-tyrosine is administered in conjunction with any combination of levodopa, levodopa analog or dopaminergic containing medicines, MAO-B inhibitors and/or COMT inhibitors. 
     
     
         29 . The method of  claim 25 , wherein the levodopa, levodopa analog or dopaminergic containing medication, MAO-B inhibitors and/or COMT inhibitors doses are adjusted during the initiation and ongoing administration of alpha-methyl-p-tyrosine as clinically indicated. 
     
     
         30 . The method of  claim 17 , wherein alpha-methyl-p-tyrosine is administered in conjunction with VMAT2 inhibitor(s). 
     
     
         31 . The method of  claim 17 , wherein alpha-methyl-p-tyrosine is deuterated in one or more positions where metabolism of alpha-methyl-p-tyrosine involves hydroxylation and/or carbonylation. 
     
     
         32 . The method of  claim 14 , wherein alpha-methyl-p-tyrosine is administered in halide-substituted form. 
     
     
         33 . The method of  claim 32 , wherein the halide is fluoride, chloride, bromide and/or iodide. 
     
     
         34 . The method of  claim 32 , wherein the halide form of alpha-methyl-p-tyrosine is deuterated in one or more positions where metabolism of alpha-methyl-p-tyrosine involves hydroxylation and/or carbonylation. 
     
     
         35 . The method of  claim 33 , wherein the halide is in the 3′ position of the benzene ring. 
     
     
         36 . The method of  claim 33 , wherein the halide is in the 5′ position of the benzene ring. 
     
     
         37 . The method of  claim 33 , wherein halide substation is in both the 3′ and 5′ positions. 
     
     
         38 . The method of  claim 37 , wherein dihalide substitution of alpha-methyl-p-tyrosine is with the same halide. 
     
     
         39 . The method of  claim 37 , wherein dihalide substitution of alpha-methyl-p-tyrosine is with the different halides. 
     
     
         40 . The method of  claim 14 , wherein alpha-methyl-p-tyrosine is administered in methyl-substituted form. 
     
     
         41 . The method of  claim 40 , wherein the methylated form of alpha-methyl-p-tyrosine is deuterated in one or more positions where metabolism of alpha-methyl-p-tyrosine involves hydroxylation and/or carbonylation. 
     
     
         42 . The method of  claim 14 , wherein tyrosine hydroxylase inhibition is via administration of one or more of methyl (2R)-2-amino-3-(2-chloro-4 hydroxyphenyl) propanoate, D-tyrosine ethyl ester hydrochloride, methyl (2R)-2-amino-3-(2,6-dichloro-3,4-dimethoxyphenyl) propanoate H-D-Tyr(TBU)-allyl ester HCl, methyl (2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl) propanoate, methyl (2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(4-[(2-chloro-6-fluorophenyl)methoxy]phenyl) propanoate, methyl (2R)-2-amino-3-(2-chloro-3,4-dimethoxyphenyl) propanoate, methyl (2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl) propanoate, diethyl 2-(acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl) oxy]benzyl malonate, methyl (2R)-2-amino-3-(3-chloro-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(3-chloro-4-hydroxy-5-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(2,6-dichloro-3-hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(3-chloro-4-hydroxyphenyl) propanoate, H-DL-tyr-OME HCl, H-3,5-diiodo-tyr-OME HCl, H-D-3,5-diiodo-tyr-OME HCl, H-D-tyr-OME HCl, D-tyrosine methyl ester hydrochloride, D-tyrosine-ome HCl, methyl D-tyrosinate hydrochloride, H-D-tyr-OMe-HCl, D-tyrosine methyl ester HCl, H-D-Tyr-OMe-HCl, (2R)-2-amino-3-(4-hydroxyphenyl) propionic acid, (2R)-2-amino-3-(4-hydroxyphenyl) methyl ester hydrochloride, methyl (2R)-2-amino-3-(4-hydroxyphenyl) propanoate hydrochloride, methyl (2R)-2-azanyl-3-(4-hydroxyphenyl) propanoate hydrochloride, 3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl ester hydrochloride, DL-m-tyrosine, DL-o-tyrosine, Boc-Tyr (3,5-I2)-oSu, Fmoc-tyr(3-NO2)-OH, α-methyl-L-tyrosine, α-methyl-D-tyrosine and/or α-methyl-DL-tyrosine. 
     
     
         43 . The method of  claim 35 , wherein the dose ranges are from 1 μg to 25 g per day for each of these compounds. 
     
     
         44 . The method of  claim 14 , wherein the tyrosine hydroxylase inhibitor is one or more of aquayamycin, bulbocapnine, oudenone, 3-iodotyrosine, L-tryptophan, L-phenylalanine, DL-p-fluoro-phenylalanine, and/or 3,4-dihydroxyphenyl-propyl-acetamide (H-22/54). 
     
     
         45 . The method of  claim 44 , wherein the dose ranges are from 1 μg to 25 g per day for each of these compounds. 
     
     
         46 . The method of  claim 44 , wherein each or any of the tyrosine hydroxylase inhibitors are deuterated at one or more sites wherein the halide form of alpha-methyl-p-tyrosine is deuterated in one or more positions where metabolism of alpha-methyl-p-tyrosine involved hydroxylation and/or carbonylation. 
     
     
         47 . The method of  claim 15 , wherein biosynthesis of the tyrosine hydroxylase cofactor tetrahydrobiopterin is via administration of one or more of sulfathiazole, sulfamethoxazole, sulfadiazine and/or methotrexate. 
     
     
         48 . The method of  claim 47 , wherein the dose ranges are from 1 μg to 25 g per day for each of these compounds. 
     
     
         49 . The method of  claim 15 , wherein methotrexate is administered less frequently than each day, including weekly, monthly and/or intermittently based on clinical condition. 
     
     
         50 . The method of  claim 17 , wherein alpha-methyl-p-tyrosine is administered with a urinary alkalinizing agent. 
     
     
         51 . The method of  claim 50 , wherein the alkalinizing agent is one or more of sodium bicarbonate, calcium carbonate, sodium citrate, potassium citrate and/or calcium citrate. 
     
     
         52 . The method of  claim 51 , wherein the dose ranges are from 5 to 300 mEq/day. 
     
     
         53 . The method of  claim 1 , wherein tyrosine hydroxylase inhibition is achieved via combination of a tyrosine hydroxylase inhibitor with inhibitor of tetrahydrobiopterin biosynthesis.