Bis-pyridino containing compounds for the use in the treatment of CNS pathologies

Abstract

N-n-Alkylation of nicotine converts nicotine from an agonist into an antagonist specifically for neuronal nicotinic acetylcholine receptor subtypes mediating nicotine-evoked dopamine release. Conformationally restricted analogs exhibit both high affinity and selectivity at this site, and are able to access the brain due to their ability to act as substrates for the blood-brain barrier choline transporter.

1 . A nicotine antagonist having the formula  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 2 , R 3 , R 4 , R 5 , R 6  are each independently selected from hydrogen; alkyl; substituted alkyl; cycloalkyl; substituted cycloalkyl, pyrrolidine; N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; unsaturated pyrrolidine; unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; aziridine; N-methyl aziridine; azetidine; N-methyl azetidine; unsaturated azetidine; unsaturated N-methyl azetidine; piperidine; N-methyl piperidine; unsaturated piperidine; unsaturated N-methyl piperidine; azepane; N-methyl azepane; unsaturated azepane; unsaturated N-methyl azepane; azocane; N-methyl azocane; unsaturated azocane; unsaturated N-methyl azocane; 1-aza-bicyclo[3.2.1]octane; 1-aza-bicyclo[2.2.1]heptane; 8-methyl-8-aza-bicyclo[3.2.1]octane; 1-aza-tricyclo[3.3.1.1]decane; methyl cycloalkyl; methyl substituted cycloalkyl, methyl pyrrolidine; methyl N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; methyl unsaturated pyrrolidine; methyl unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; methyl aziridine; methyl N-methyl aziridine; methyl azetidine; methyl N-methyl azetidine; methyl unsaturated azetidine; methyl unsaturated N-methyl azetidine; methyl piperidine; methyl N-methyl piperidine; methyl unsaturated piperidine; methyl unsaturated N-methyl piperidine; methyl azepane; methyl N-methyl azepane; methyl unsaturated azepane; methyl unsaturated N-methyl azepane; methyl azocane; methyl N-methyl azocane; methyl unsaturated azocane; methyl unsaturated N-methyl azocane; methyl 1-aza-bicyclo[3.2.1]octane; methyl 1-aza-bicyclo[2.2.1]heptane; 8-methyl-8-aza-bicyclo[3.2.1]octane; methyl 1-aza-tricyclo[3.3.1.1]decane;  
 R 1  is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, subtituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, alkoxy, alkylamine, thioalkyl; and  
 X is selected from Cl, Br, I, HSO 4 , ½SO 2 , CH 3 SO 3 , p-TsO, CF 3 SO 3  and any ion that completes the salt form of the nicotine antagonist; and enantomers, diastereomers and racemic mixes thereof.  
 
   
   
       2 . The nicotine antagonist of  claim 1  wherein one or more of R2 and R3, R3 and R4, R4 and R5, and R5 and R6 form a fused aromatic or unsaturated ring, Z.  
   
   
       3 . The nicotine antagonist of  claim 2  wherein the ring, Z, is selected from (CH 2 ) n  where n=3-8, benzene, pyridine, pyran, indene, isoindene, benzofuran, isobenzofuran, benzo[b]thiophene, benzo[c]thiophene, indole, indolenine, isoindole, cyclopental[b]pyridine, pyrano[3,4-b]pyrrole, indazole, indoxazine, benzosazole, anthranil, naphthalene, tetralin, decalin, chromene, coumarin, chroman-4-one, isocoumarin, isochromen-3-one, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, pyrido[3,4-b]-pyridine, pyridol[3,2-b]pyridine, pyrido[4,3,-b]-pyridine, benzoxazine, anthracene, phenanthrene, phenalene, fluorene, carazole, xanthene, acridine, octahydro-[1]pyridine, 1-methyl octahydro-[1]pyridine, octahydro-indole, 1-methyl octahydro-indole, octahydro-cyclopenta[b]pyrrole, 1methyl-octahydro-cyclopenta[b]pyrrole, decahydro-quinoline, 1-methyl-decahydro-quinoline including all possible substitution patterns, and geometric isomers, stereoisomers, racemic, diastereomeric and enantiomeric forms thereof.  
   
   
       4 . The nicotine antagonist of  claim 1  wherein Ring 1 and Ring 2 are identical.  
   
   
       5 . The nicotine antagonist of claim I wherein Ring 1 and Ring 2 are independently unsaturated nitrogen heterocyclic rings.  
   
   
       6 . The nicotine antagonist of  claim 5  wherein Ring 1 and R2 are independently selected from pyrrole, pyrrolidine, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazine, including all possible substitution patterns, geometric and stereoisomers, racemic, diastereomeric and enantiomeric forms thereof.  
   
   
       7 . The nicotine antagonist of  claim 1  wherein R 2 , R 4 , R 5 , R 6  are individually selected from the group consisting of hydrogen, halogen, alkyl or alkanoyl.  
   
   
       8 . The nicotine antagonist of  claim 1  wherein R 3  is selected from the group consisting of hydrogen, halogen, alkyl, alkanoyl, amino, alkylamino, piperidine, N-methyl piperidine, pyrrolidine, N-methyl pyrrolidine or quinuclidine.  
   
   
       9 . The nicotine antagonist of  claim 1  wherein R 1  is a branched or non-branched C 4 -C 19  alkyl.  
   
   
       10 . The nicotine antagonist of  claim 1  wherein X is iodine or bromine.  
   
   
       11 . The nicotine antagonist of  claim 1  selected from the group consisting of 
 N,N′-Pentane-1,5-diyl-bis-pyridinium; Diiodide (bPPeI),    N,N′-Hexane-1,6-diyl-bis-pyridinium; Diiodide (bPHxI),    N,N′-Octane-1,8-diyl-bis-pyridinium; Diiodide (bPOI),    N,N′-Nonane-1,9-diyl-bis-pyridinium; Dibromide (bPNB),    N,N′-Decane-1,10-diyl-bis-pyridinium; Diiodide (bPDI),    N,N′-Undecane-1,11-diyl-bis-pyridinium; Dibromide (bPUB),    N,N′-Dodecane-1,12-diyl-bis-pyridinium; Dibromide (bPDDB),    N,N′-Hexane-1,6-diyl-bis-picolinium; Diiodide (bPiHxI),N,N′-Octane-1,8-diyl-bis-picolinium; Diiodide (bPiOI),    N,N′-Nonane-1,9-diyl-bis-picolinium; Dibromide (bPiNB),    N,N′-Decane-1,10-diyl-bis-picolinium; Diiodide(bPiDI),    N,N′-Undecane-1,11-diyl-bis-picolinium; Dibromide (bPiUB),    N,N′-Dodecane-1,12-diyl-bis-picolinium; Dibromide (bPiDDB),    N,N′-Hexane-1,6-diyl-bis-quinolinium; Diiodide (bQHxI),    N,N′-Octane-1,8-diyl-bis-quinolinium; Diiodide (bQOI),    N,N′-Nonane-1,9-diyl-bis-quinolinium; Dibromide (bQNB),    N,N′-Decane-1,10-diyl-bis-quinolinium; Diiodide(bQDI),    N,N′-Undecane-1,11-diyl-bis-quinolinium; Dibromide (bQUB),    N,N′-Dodecane-1,12-diyl-bis-quinolinium; Dibromide (bQDDB),    N,N′-Hexane-1,6-diyl-bis-isoquinolinium; Diiodide (bIQHxI),    N,N′-Octane-1,8-diyl-bis-isoquinolinium; Diiodide (bIQOI),    N,N′-Nonane-1,9-diyl-bis-isoquinolinium; Dibromide (bIQNB),    N,N′-Decane-1,10-diyl-bis-isoquinolinium; Diiodide(bIQDI),    N,N′-Undecane-1,11-diyl-bis-isoquinolinium; Dibromide (bIQUB),    N,N′-Dodecane-1,12-diyl-bis-isoquinolinium; Dibromide (bIQDDB),    N,N′-Hexane-1,6-diyl-bis-nicotinium; Diiodide (bNHxI),    N,N′-Octane-1,8-diyl-bis-nicotinium; Diiodide (bNOI),    N,N′-Nonane-1,9-diyl-bis-nicotinium; Dibromide(bNNB),    N,N′-Decane-1,10-diyl-bis-nicotinium; Diiodide(bNDI),    N,N′-Undecane-1,11-diyl-bis-nicotinium; Dibromide(bNUB), and    N,N′-Dodecane-1,12-diyl-bis-nicotinium; Dibromide(bNDDB).    
   
   
       12 . The nicotine antagonist of  claim 1  wherein the nicotine antagonist is N,N′-dodecyl-bis-picolinium bromide (bPiDDB).  
   
   
       13 . A composition for treating nicotine addiction comprising at least one nicotine antagonist having the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 2 , R 3 , R 4 , R 5 , R 6  are each independently selected from hydrogen; alkyl; substituted alkyl; cycloalkyl; substituted cycloalkyl, pyrrolidine; N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; unsaturated pyrrolidine; unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; aziridine; N-methyl aziridine; azetidine; N-methyl azetidine; unsaturated azetidine; unsaturated N-methyl azetidine; piperidine; N-methyl piperidine; unsaturated piperidine; unsaturated N-methyl piperidine; azepane; N-methyl azepane; unsaturated azepane; unsaturated N-methyl azepane; azocane; N-methyl azocane; unsaturated azocane; unsaturated N-methyl azocane; 1-aza-bicyclo[3.2.1]octane; 1-aza-bicyclo[2.2.1]heptane; 8-methyl-8-aza-bicyclo[3.2.1]octane; 1-aza-tricyclo[3.3.1.1]decane; methyl cycloalkyl; methyl substituted cycloalkyl, methyl pyrrolidine; methyl N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; methyl unsaturated pyrrolidine; methyl unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; methyl aziridine; methyl N-methyl aziridine; methyl azetidine; methyl N-methyl azetidine; methyl unsaturated azetidine; methyl unsaturated N-methyl azetidine; methyl piperidine; methyl N-methyl piperidine; methyl unsaturated piperidine; methyl unsaturated N-methyl piperidine; methyl azepane; methyl N-methyl azepane; methyl unsaturated azepane; methyl unsaturated N-methyl azepane; methyl azocane; methyl N-methyl azocane; methyl unsaturated azocane; methyl unsaturated N-methyl azocane; methyl 1-aza-bicyclo[3.2.1]octane; methyl 1-aza- bicyclo[2.2.1]heptane; 8-methyl-8-aza-bicyclo[3.2.1]octane; methyl 1-aza-tricyclo[3.3.1.1]decane;  
 R 1  is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, subtituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, alkoxy, alkylamine, thioalkyl; and  
 X is selected from Cl, Br, I, HSO 4 , ½SO 2 , CH 3 SO 3 , p-TsO, CF 3 SO 3  and any ion that completes the salt form of the nicotine antagonist; and enantomers, diastereomers and racemic mixes thereof.  
 
   
   
       14 . The composition of  claim 13  wherein wherein one or more of R2 and R3, R3 and R4, R4 and R5, and R5 and R6 form a fused aromatic or unsaturated ring, Z.  
   
   
       15 . The composition of  claim 13  wherein the ring, Z, is selected from (CH 2 ) n  where n=3-8, benzene, pyridine, pyran, indene, isoindene, benzofuran, isobenzofuran, benzo[b]thiophene, benzo[c]thiophene, indole, indolenine, isoindole, cyclopental[b]pyridine, pyrano[3,4-b]pyrrole, indazole, indoxazine, benzosazole, anthranil, naphthalene, tetralin, decalin, chromene, coumarin, chroman-4-one, isocoumarin, isochromen-3-one, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, pyrido[3,4-b]-pyridine, pyridol[3,2-b]pyridine, pyrido[4,3,-b]-pyridine, benzoxazine, anthracene, phenanthrene, phenalene, fluorene, carazole, xanthene, acridine, octahydro-[1]pyridine, 1-methyl octahydro-[1]pyridine, octahydro-indole, 1-methyl octahydro-indole, octahydro-cyclopenta[b]pyrrole, 1methyl-octahydro-cyclopenta[b]pyrrole, decahydro-quinoline, 1-methyl-decahydro-quinoline including all possible substitution patterns, and geometric isomers, stereoisomers, racemic, diastereomeric and enantiomeric forms thereof.  
   
   
       16 . The composition of  claim 13  wherein Ring 1 and Ring 2 are identical.  
   
   
       17 . The composition of  claim 13  wherein Ring 1 and Ring 2 are independently unsaturated nitrogen heterocyclic rings.  
   
   
       18 . The composition of  claim 17  wherein Ring 1 and R2 are independently selected from pyrrole, pyrrolidine, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazine, including all possible substitution patterns, geometric and stereoisomers, racemic, diastereomeric and enantiomeric forms thereof.  
   
   
       19 . The nicotine antagonist of  claim 1  wherein R 2 , R 4 , R 5 , R 6  are individually selected from the group consisting of hydrogen, halogen, alkyl or alkanoyl.  
   
   
       20 . The composition of  claim 13  wherein R 3  is selected from the group consisting of hydrogen, halogen, alkyl, alkanoyl, amino, alkylamino, piperidine, N-methyl piperidine, pyrrolidine, N-methyl pyrrolidine or quinuclidine.  
   
   
       21 . The composition onist of  claim 13  wherein R 1  is a branched or non-branched C 4 -C 19  alkyl.  
   
   
       22 . The composition of  claim 13  wherein X is iodine or bromine.  
   
   
       23 . The composition of  claim 13  wherein the nicotine antagonist elected from the group consisting of: 
 N,N′-Pentane-1,5-diyl-bis-pyridinium; Diiodide (bPPeI),    N,N′-Hexane-1,6-diyl-bis-pyridinium; Diiodide (bPHxI),    N,N′-Octane-1,8-diyl-bis-pyridinium; Diiodide (bPOI),    N,N′-Nonane-1,9-diyl-bis-pyridinium; Dibromide (bPNB),    N,N′-Decane-1,10-diyl-bis-pyridinium; Diiodide (bPDI),    N,N′-Undecane-1,11-diyl-bis-pyridinium; Dibromide (bPUB),    N,N′-Dodecane-1,12-diyl-bis-pyridinium; Dibromide (bPDDB),    N,N′-Hexane-1,6-diyl-bis-picolinium; Diiodide (bPiHxI),N,N′-Octane-1,8-diyl-bis-picolinium; Diiodide (bPiOI),    N,N′-Nonane-1,9-diyl-bis-picolinium; Dibromide (bPiNB),    N,N′-Decane-1,10-diyl-bis-picolinium; Diiodide(bPiDI),    N,N′-Undecane-1,11-diyl-bis-picolinium; Dibromide (bPiUB),    N,N′-Dodecane-1,12-diyl-bis-picolinium; Dibromide (bPiDDB),    N,N′-Hexane-1,6-diyl-bis-quinolinium; Diiodide (bQHxI),    N,N′-Octane-1,8-diyl-bis-quinolinium; Diiodide (bQOI),    N,N′-Nonane-1,9-diyl-bis-quinolinium; Dibromide (bQNB),    N,N′-Decane-1,10-diyl-bis-quinolinium; Diiodide(bQDI),    N,N′-Undecane-1,11-diyl-bis-quinolinium; Dibromide (bQUB),    N,N′-Dodecane-1,12-diyl-bis-quinolinium; Dibromide (bQDDB),    N,N′-Hexane-1,6-diyl-bis-isoquinolinium; Diiodide (bIQHxI),    N,N′-Octane-1,8-diyl-bis-isoquinolinium; Diiodide (bIQOI),    N,N′-Nonane-1,9-diyl-bis-isoquinolinium; Dibromide (bIQNB),    N,N′-Decane-1,10-diyl-bis-isoquinolinium; Diiodide(bIQDI),    N,N′-Undecane-1,1 1-diyl-bis-isoquinolinium; Dibromide (bIQUB),    N,N′-Dodecane-1,12-diyl-bis-isoquinolinium; Dibromide (bIQDDB),    N,N′-Hexane-1,6-diyl-bis- nicotinium; Diiodide (bNHxI),    N,N′-Octane-1,8-diyl-bis-nicotinium; Diiodide (bNOI),    N,N′-Nonane-1,9-diyl-bis-nicotinium; Dibromide(bNNB),    N,N′-Decane-1,10-diyl-bis-nicotinium; Diiodide(bNDI),    N,N′-Undecane-1,11-diyl-bis-nicotinium; Dibromide(bNUB), and    N,N′-Dodecane-1,12-diyl-bis-nicotinium; Dibromide(bNDDB).    
   
   
       24 . The composition of  claim 13  wherein the nicotine antagonist is N,N′-dodecyl-bis-picolinium bromide (bPiDDB).  
   
   
       25 . A method of treating nicotine addiction comprising administering to a patient a compomposition comprising an effective amount of at least one nicotine antagonist having the formula  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 2 , R 3 , R 4 , R 5 , R 6  are each independently selected from hydrogen; alkyl; substituted alkyl; cycloalkyl; substituted cycloalkyl, pyrrolidine; N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; unsaturated pyrrolidine; unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; aziridine; N-methyl aziridine; azetidine; N-methyl azetidine; unsaturated azetidine; unsaturated N-methyl azetidine; piperidine; N-methyl piperidine; unsaturated piperidine; unsaturated N-methyl piperidine; azepane; N-methyl azepane; unsaturated azepane; unsaturated N-methyl azepane; azocane; N-methyl azocane; unsaturated azocane; unsaturated N-methyl azocane; 1-aza-bicyclo[3.2.1]octane; 1-aza-bicyclo[2.2.2]heptane; 8-methyl-8-aza-bicyclo[3.2.1]octane; 1-aza-tricyclo[3.3.1.1]decane; methyl cycloalkyl; methyl substituted cycloalkyl, methyl pyrrolidine; methyl N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; methyl unsaturated pyrrolidine; methyl unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; methyl aziridine; methyl N-methyl aziridine; methyl azetidine; methyl N-methyl azetidine; methyl unsaturated azetidine; methyl unsaturated N-methyl azetidine; methyl piperidine; methyl N-methyl piperidine; methyl unsaturated piperidine; methyl unsaturated N-methyl piperidine; methyl azepane; methyl N-methyl azepane; methyl unsaturated azepane; methyl unsaturated N-methyl azepane; methyl azocane; methyl N-methyl azocane; methyl unsaturated azocane; methyl unsaturated N-methyl azocane; methyl 1-aza-bicyclo[3.2.1]octane; methyl 1-aza-bicyclo[2.2.1]heptane; 8-methyl-8-aza-bicyclo[3.2.1]octane; methyl 1-aza-tricyclo[3.3.1.1]decane;  
 R 1  is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, subtituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, alkoxy, alkylamine, thioalkyl; and  
 X is selected from Cl, Br, I, HSO 4 , ½SO 2 , CH 3 SO 3 , p-TsO, CF 3 SO 3  and any ion that completes the salt form of the nicotine antagonist; and enantomers, diastereomers and racemic mixes thereof.  
 
   
   
       26 . The method of  claim 25  wherein wherein one or more of R2 and R3, R3 and R4, R4 and R5, and R5 and R6 form a fused aromatic or unsaturated ring, Z.  
   
   
       27 . The method of  claim 25  wherein the ring, Z, is selected from (CH 2 ) n  where n=3-8, benzene, pyridine, pyran, indene, isoindene, benzofuran, isobenzofuran, benzo[b]thiophene, benzo[c]thiophene, indole, indolenine, isoindole, cyclopental[b]pyridine, pyrano[3,4-b]pyrrole, indazole, indoxazine, benzosazole, anthranil, naphthalene, tetralin, decalin, chromene, coumarin, chroman-4-one, isocoumarin, isochromen-3-one, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, pyrido[3,4-b]-pyridine, pyridol[3,2-b]pyridine, pyrido[4,3,-b]-pyridine, benzoxazine, anthracene, phenanthrene, phenalene, fluorene, carazole, xanthene, acridine, octahydro-[1]pyridine, 1-methyl octahydro-[1]pyridine, octahydro-indole, 1-methyl octahydro-indole, octahydro-cyclopenta[b]pyrrole, 1methyl-octahydro-cyclopenta[b]pyrrole, decahydro-quinoline, 1-methyl-decahydro-quinoline including all possible substitution patterns, and geometric isomers, stereoisomers, racemic, diastereomeric and enantiomeric forms thereof.  
   
   
       28 . The method of  claim 25  wherein Ring 1 and Ring 2 are identical.  
   
   
       29 . The method of  claim 25  wherein Ring 1 and Ring 2 are independently unsaturated nitrogen heterocyclic rings.  
   
   
       30 . The method of  claim 29  wherein Ring 1 and R2 are independently selected from pyrrole, pyrrolidine, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazine, including all possible substitution patterns, geometric and stereoisomers, racemic, diastereomeric and enantiomeric forms thereof.  
   
   
       31 . The method of  claim 25  wherein R 2 , R 4 , R 5 , R 6  are individually selected from the group consisting of hydrogen, halogen, alkyl or alkanoyl.  
   
   
       32 . The method  claim 25  wherein R 3  is selected from the group consisting of hydrogen, halogen, alkyl, alkanoyl, amino, alkylamino, piperidine, N-methyl piperidine,  
   
   
       33 . The method of  claim 25  wherein R 1  is a branched or non-branched C 4 -C 19  alkyl.  
   
   
       34 . The method of  claim 25  wherein X is iodine or bromine.  
   
   
       35 . The method of  claim 25  wherein the nicotine antagonist is selected from the group consisting of: 
 N,N′-Pentane-1,5-diyl-bis-pyridinium; Diiodide (bPPeI),    N,N′-Hexane-1,6-diyl-bis-pyridinium; Diiodide (bPHxI),    N,N′-Octane-1,8-diyl-bis-pyridinium; Diiodide (bPOI),    N,N′-Nonane-1,9-diyl-bis-pyridinium; Dibromide (bPNB),    N,N′-Decane-1,10-diyl-bis-pyridinium; Diiodide (bPDI),    N,N′-Undecane-1,11-diyl-bis-pyridinium; Dibromide (bPUB),    N,N′-Dodecane-1,12-diyl-bis-pyridinium; Dibromide (bPDDB),    N,N′-Hexane-1,6-diyl-bis-picolinium; Diiodide (bPiHxI),N,N′-Octane-1,8-diyl-bis-picolinium; Diiodide (bPiOI),    N,N′-Nonane-1,9-diyl-bis-picolinium; Dibromide (bPiNB),    N,N′-Decane-1,10-diyl-bis-picolinium; Diiodide(bPiDI),    N,N′-Undecane-1,11-diyl-bis-picolinium; Dibromide (bPiUB),    N,N′-Dodecane-1,12-diyl-bis-picolinium; Dibromide (bPiDDB),    N,N′-Hexane-1,6-diyl-bis-quinolinium; Diiodide (bQHxI),    N,N′-Octane-1,8-diyl-bis-quinolinium; Diiodide (bQOI),    N,N′-Nonane-1,9-diyl-bis-quinolinium; Dibromide (bQNB),    N,N′-Decane-1,10-diyl-bis-quinolinium; Diiodide(bQDI),    N,N′-Undecane-1,11-diyl-bis-quinolinium; Dibromide (bQUB),    N,N′-Dodecane-1,12-diyl-bis-quinolinium; Dibromide (bQDDB),    N,N′-Hexane-1,6-diyl-bis-isoquinolinium; Diiodide (bIQHxI),    N,N′-Octane-1,8-diyl-bis-isoquinolinium; Diiodide (bIQOI),    N,N′-Nonane-1,9-diyl-bis-isoquinolinium; Dibromide (bIQNB),    N,N′-Decane-1,10-diyl-bis-isoquinolinium; Diiodide(bIQDI),    N,N′-Undecane-1,11-diyl-bis-isoquinolinium; Dibromide (bIQUB),    N,N′-Dodecane-1,12-diyl-bis-isoquinolinium; Dibromide (bIQDDB),    N,N′-Hexane-1,6-diyl-bis- nicotinium; Diiodide (bNHxI),    N,N′-Octane-1,8-diyl-bis-nicotinium; Diiodide (bNOI),    N,N′-Nonane-1,9-diyl-bis-nicotinium; Dibromide(bNNB),    N,N′-Decane-1,10-diyl-bis-nicotinium; Diiodide(bNDI),    N,N′-Undecane-1,11-diyl-bis-nicotinium; Dibromide(bNUB), and    N,N′-Dodecane-1,12-diyl-bis-nicotinium; Dibromide(bNDDB).    
   
   
       36 . The method of  claim 25  wherein the composition comprises N,N′-dodecyl-bis-picolinium bromide (bPiDDB).  
   
   
       37 . The method of  claim 25  wherein the composition is administered orally, sublingually, or via a topical patch, nasal spray, injection, or suppository.  
   
   
       38 . A method of treating a dopamine mediated disease state comprising administering to an individual an effective amount of a composition comprising at least one nicotine antagonist having the formula  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 2 , R 3 , R 4 , R 5 , R 6  are each independently selected from hydrogen; alkyl; substituted alkyl; cycloalkyl; substituted cycloalkyl, pyrrolidine; N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; unsaturated pyrrolidine; unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; aziridine; N-methyl aziridine; azetidine; N-methyl azetidine; unsaturated azetidine; unsaturated N-methyl azetidine; piperidine; N-methyl piperidine; unsaturated piperidine; unsaturated N-methyl piperidine; azepane; N-methyl azepane; unsaturated azepane; unsaturated N-methyl azepane; azocane; N-methyl azocane; unsaturated azocane; unsaturated N-methyl azocane; 1-aza-bicyclo[3.2.1]octane; 1-aza-bicyclo[2.2.1]heptane; 8-methyl-8-aza-bicyclo[3.2.1]octane; 1-aza-tricyclo[3.3.1.1]decane; methyl cycloalkyl; methyl substituted cycloalkyl, methyl pyrrolidine; methyl N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; methyl unsaturated pyrrolidine; methyl unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; methyl aziridine; methyl N-methyl aziridine; methyl azetidine; methyl N-methyl azetidine; methyl unsaturated azetidine; methyl unsaturated N-methyl azetidine; methyl piperidine; methyl N-methyl piperidine; methyl unsaturated piperidine; methyl unsaturated N-methyl piperidine; methyl azepane; methyl N-methyl azepane; methyl unsaturated azepane; methyl unsaturated N-methyl azepane; methyl azocane; methyl N-methyl azocane; methyl unsaturated azocane; methyl unsaturated N-methyl azocane; methyl 1-aza-bicyclo[3.2.1]octane; methyl 1-aza-bicyclo[2.2.1]heptane; 8-methyl-8-aza-bicyclo[3.2.1]octane; methyl 1-aza-tricyclo[3.3.1.1]decane;  
 R 1  is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, subtituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, alkoxy, alkylamine, thioalkyl; and  
 X is selected from Cl, Br, I, HSO 4 , ½SO 2 , CH 3 SO 3 , p-TsO, CF 3 SO 3  and any ion that completes the salt form of the nicotine antagonist; and enantomers, diastereomers and racemic mixes thereof.  
 
   
   
       39 . The method of  claim 38  wherein the dopamine mediated disease state is selected from the group consisting of myasthenia gravis, Parkinson's disease, Alzheimer's disease, schizophrenia, eating disorders, and drug addiction.  
   
   
       40 . The method of  claim 39  wherein said drug addiction is to a drug selected from the group consisting of nicotinic agonists, cocaine, amphetamines, caffeine, phencyclidine, opiates, barbituates, benzodiazepines, cannabinoids, hallucinogens and alcohol.  
   
   
       41 . The method of  claim 39  wherein the composition is administered orally, transdermally, transnasally, rectally, sublinguinally, subdermally, intraocularly or via smokeless inhalation.  
   
   
       42 . A method of displacing nicotine from nicotinic receptor sites in the brain comprising administering to an individual in need of such treatment an effective amount of a composition comprising at least one nicotine antagonist having the formula  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 2 , R 3 , R 4 , R 5 , R 6  are each independently selected from hydrogen; alkyl; substituted alkyl; cycloalkyl; substituted cycloalkyl, pyrrolidine; N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; unsaturated pyrrolidine; unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; aziridine; N-methyl aziridine; azetidine; N-methyl azetidine; unsaturated azetidine; unsaturated N-methyl azetidine; piperidine; N-methyl piperidine; unsaturated piperidine; unsaturated N-methyl piperidine; azepane; N-methyl azepane; unsaturated azepane; unsaturated N-methyl azepane; azocane; N-methyl azocane; unsaturated azocane; unsaturated N-methyl azocane; 1-aza-bicyclo[3.2.1]octane; 1-aza-bicyclo[2.2.1]heptane; 8-methyl-8-aza-bicyclo[3.2.1 ]octane; 1-aza-tricyclo[3.3.1.1]decane; methyl cycloalkyl; methyl substituted cycloalkyl, methyl pyrrolidine; methyl N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; methyl unsaturated pyrrolidine; methyl unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; methyl aziridine; methyl N-methyl aziridine; methyl azetidine; methyl N-methyl azetidine; methyl unsaturated azetidine; methyl unsaturated N-methyl azetidine; methyl piperidine; methyl N-methyl piperidine; methyl unsaturated piperidine; methyl unsaturated N-methyl piperidine; methyl azepane; methyl N-methyl azepane; methyl unsaturated azepane; methyl unsaturated N-methyl azepane; methyl azocane; methyl N-methyl azocane; methyl unsaturated azocane; methyl unsaturated N-methyl azocane; methyl 1-aza-bicyclo[3.2.1]octane; methyl 1-aza-bicyclo[2.2.1]heptane; 8-methyl-8-aza-bicyclo[3.2.1]octane; methyl 1-aza-tricyclo[3.3.1.1]decane;  
 R 1  is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, subtituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, alkoxy, alkylamine, thioalkyl; and  
 X is selected from Cl, Br, I, HSO 4 , ½SO 2 , CH 3 SO 3 , p-TsO, CF 3 SO 3  and any ion that completes the salt form of the nicotine antagonist; and enantomers, diastereomers and racemic mixes thereof;  
 wherein said composition is administered outside the central nervous system and in an amount sufficient to cross the blood-brain barrier.  
 
   
   
       43 . A method of obtaining dopamine release from presynaptic terminals in neuronal dopamine tissue in a stereoselective and receptor-mediated manner comprising administering to an individual in need of such treatment an effective amount of a composition comprising at least one nicotine antagonist having the formula  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 2 , R 3 , R 4 , R 5 , R 6  are each independently selected from hydrogen; alkyl; substituted alkyl; cycloalkyl; substituted cycloalkyl, pyrrolidine; N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; unsaturated pyrrolidine; unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; aziridine; N-methyl aziridine; azetidine; N-methyl azetidine; unsaturated azetidine; unsaturated N-methyl azetidine; piperidine; N-methyl piperidine; unsaturated piperidine; unsaturated N-methyl piperidine; azepane; N-methyl azepane; unsaturated azepane; unsaturated N-methyl azepane; azocane; N-methyl azocane; unsaturated azocane; unsaturated N-methyl azocane; 1-aza-bicyclo[3.2.1]octane; 1-aza-bicyclo[2.2.1]heptane; 8-methyl-8-aza-bicyclo[3.2.1]octane; 1-aza-tricyclo[3.3.1.1]decane; methyl cycloalkyl; methyl substituted cycloalkyl, methyl pyrrolidine; methyl N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; methyl unsaturated pyrrolidine; methyl unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; methyl aziridine; methyl N-methyl aziridine; methyl azetidine; methyl N-methyl azetidine; methyl unsaturated azetidine; methyl unsaturated N-methyl azetidine; methyl piperidine; methyl N-methyl piperidine; methyl unsaturated piperidine; methyl unsaturated N-methyl piperidine; methyl azepane; methyl N-methyl azepane; methyl unsaturated azepane; methyl unsaturated N-methyl azepane; methyl azocane; methyl N-methyl azocane; methyl unsaturated azocane; methyl unsaturated N-methyl azocane; methyl 1-aza-bicyclo[3.2.1]octane; methyl 1-aza-bicyclo[2.2.1]heptane; 8-methyl-8-aza-bicyclo[3.2.1]octane; methyl 1-aza-tricyclo[3.3.1.1]decane;  
 R 1  is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, subtituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, alkoxy, alkylamine, thioalkyl; and  
 X is selected from Cl, Br, I, HSO 4 , ½SO 2 , CH 3 SO 3 , p-TsO, CF 3 SO 3  and any ion that completes the salt form of the nicotine antagonist; and enantomers, diastereomers and racemic mixes thereof, to obtain dopamine release, said composition being administered outside the central nervous system and in an amount sufficient to cross the blood-brain barrier.  
 
   
   
       44 . A method of activating the mechanism involved in behavioral sensitization to psycho-stimulants which is correlated with craving in humans comprising administering to an individual in need of such treatment a composition comprising at least one nicotine antagonist having the formula  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 2 , R 3 , R 4 , R 5 , R 6  are each independently selected from hydrogen; alkyl; substituted alkyl; cycloalkyl; substituted cycloalkyl, pyrrolidine; N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; unsaturated pyrrolidine; unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; aziridine; N-methyl aziridine; azetidine; N-methyl azetidine; unsaturated azetidine; unsaturated N-methyl azetidine; piperidine; N-methyl piperidine; unsaturated piperidine; unsaturated N-methyl piperidine; azepane; N-methyl azepane; unsaturated azepane; unsaturated N-methyl azepane; azocane; N-methyl azocane; unsaturated azocane; unsaturated N-methyl azocane; 1-aza-bicyclo [3.2.1]octane; 1-aza-bicyclo[2.2.1]heptane; 8-methyl-8-aza-bicyclo[3.2.1]octane; 1-aza-tricyclo[3.3.1.1]decane; methyl cycloalkyl; methyl substituted cycloalkyl, methyl pyrrolidine; methyl N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; methyl unsaturated pyrrolidine; methyl unsaturated N-alkyl pyrrolidine, where the alkyl chain is methyl, ethyl or propyl; methyl aziridine; methyl N-methyl aziridine; methyl azetidine; methyl N-methyl azetidine; methyl unsaturated azetidine; methyl unsaturated N-methyl azetidine; methyl piperidine; methyl N-methyl piperidine; methyl unsaturated piperidine; methyl unsaturated N-methyl piperidine; methyl azepane; methyl N-methyl azepane; methyl unsaturated azepane; methyl unsaturated N-methyl azepane; methyl azocane; methyl N-methyl azocane; methyl unsaturated azocane; methyl unsaturated N-methyl azocane; methyl 1-aza-bicyclo[3.2.1]octane; methyl 1-aza-bicyclo[2.2.1]heptane; 8-methyl-8-aza-bicyclo[3.2.1]octane; methyl 1-aza-tricyclo[3.3.1.1]decane;  
 R 1  is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, subtituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, alkoxy, alkylamine, thioalkyl; and  
 X is selected from Cl, Br, I, HSO 4 , ½SO 2 , CH 3 SO 3 , p-TsO, CF 3 SO 3  and any ion that completes the salt form of the nicotine antagonist; and enantomers, diastereomers and racemic mixes thereof, said nornicotine being administered outside the central nervous system and in an amount sufficient to cross the blood-brain barrier.  
 
   
   
       45 . The method of  claim 44  wherein the step of administering an effective amount comprises administering from about 0.2 to about 35 mg per kg of body weight of said composition between one and three times daily.  
   
   
       46 . The method of  claim 44  wherein the step of administering includes administering said composition transdermally.