Bis-Quaternary Ammonium Cyclophane Compounds that Interact with Neuronal Nicotinic Acetylcholine Receptors

Abstract

Provided are bis-quaternary ammonium cyclophane compounds which are modulators of nicotinic acetylcholine receptors. Also provided are methods of using the compounds for modulating the function of a nicotinic acetylcholine receptor, and for the prevention and/or treatment of central nervous system disorders, substance use and/or abuse, and or gastrointestinal tract disorders.

1 - 10 . (canceled) 
     
     
         11 . A method for selectively modulating the function of a nicotinic acetylcholine receptor comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein X 1⊖  and X 2⊖  are each independently an organic or inorganic anion; 
         wherein Q and T are each independently attached to R 1  and R 2 , and Q and T are each independently selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic; SOY 1 , SO 2 Y 1 , SO 2 OY 1  or SO 2 NHY 1 , where Y 1  is selected from hydrogen, lower alkyl, alkenyl, alkynyl or aryl, and where Y 1  is not hydrogen in SOY 1  and if Y 1  is alkenyl or alkynyl, the site of unsaturation is not conjugated with a heteroatom; COY 2 , where Y 2  is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aryloxy, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, or substituted heterocyclic, and where if Y 2  comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the carbonyl group; OY 3 , where Y 3  is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, acyl, alkylsulfonyl, arylsulfonyl, heterocyclic, or substituted heterocyclic, where if Y 3  comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the oxygen; NY 4 Y 5 , where Y 4  and Y 5  are each independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, acyl, alkylsulfonyl, arylsulfonyl, heterocyclic, or substituted heterocyclic, where if Y 4  or Y 5  comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the nitrogen; SY 6 , where Y 6  is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, or substituted heterocyclic, and where if Y 6  comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the sulfur; 
         wherein R 1  and R 2  are each independently five or six membered rings as shown in formulas (IIA) and (IIB), wherein each ring of R 1  and R 2  has one, two or three nitrogen atoms, each ring of R 1  and R 2  has one quaternized nitrogen, and two of R 3  through R 24  of each R 1  and two of R 3  through R 24  of each R 2  are replaced by one attachment to Q and one attachment to T; 
       
       
         
           
           
               
               
           
         
         wherein A 1  is carbon or nitrogen, provided that when A 1  joins a ring atom with an unsaturated bond or is a nitrogen, R 3  is absent, and when A 1  joins a ring atom with an unsaturated bond and is a nitrogen, both R 3  and R 4  are absent; 
         wherein A 2  is carbon or nitrogen, provided that when A 2  joins a ring atom with an unsaturated bond or is a nitrogen, R 5  is absent, and when A 2  joins a ring atom with an unsaturated bond and is a nitrogen, both R 5  and R 6  are absent; 
         wherein A 3  is carbon or nitrogen, provided that when A 3  joins a ring atom with an unsaturated bond or is a nitrogen, R 7  is absent, and when A 3  joins a ring atom with an unsaturated bond and is a nitrogen, both R 7  and R 8  are absent; 
         wherein A 4  is carbon or nitrogen, provided that when A 4  joins a ring atom with an unsaturated bond or is a nitrogen, R 9  is absent, and when A 4  joins a ring atom with an unsaturated bond and is a nitrogen, both R 9  and R 10  are absent; 
         wherein A 5  is carbon or nitrogen, provided that when A 5  joins a ring atom with an unsaturated bond or is a nitrogen, R 11  is absent, and when A 5  joins a ring atom with an unsaturated bond and is a nitrogen, both R 11  and R 12  are absent; 
         wherein A 6  is carbon or nitrogen, provided that when A 6  joins a ring atom with an unsaturated bond or is a nitrogen, R 13  is absent, and when A 6  joins a ring atom with an unsaturated bond and is a nitrogen, both R 13  and R 14  are absent; 
         wherein A 7  is carbon or nitrogen, provided that when A 7  joins a ring atom with an unsaturated bond or is a nitrogen, R 15  is absent, and when A 7  joins a ring atom with an unsaturated bond and is a nitrogen, both R 15  and R 16  are absent; 
         wherein A 8  is carbon or nitrogen, provided that when A 8  joins a ring atom with an unsaturated bond or is a nitrogen, R 17  is absent, and when A 8  joins a ring atom with an unsaturated bond and is a nitrogen, both R 17  and R 18  are absent; 
         wherein A 9  is carbon or nitrogen, provided that when A 9  joins a ring atom with an unsaturated bond or is a nitrogen, R 19  is absent, and when A 9  joins a ring atom with an unsaturated bond and is a nitrogen, both R 19  and R 20  are absent; 
         wherein A 10  is carbon or nitrogen, provided that when A 10  joins a ring atom with an unsaturated bond or is a nitrogen, R 21  is absent, and when A 10  joins a ring atom with an unsaturated bond and is a nitrogen, both R 21  and R 22  are absent; 
         wherein A 11  is carbon or nitrogen, provided that when A 11  joins a ring atom with an unsaturated bond or is a nitrogen, R 23  is absent, and when A 11  joins a ring atom with an unsaturated bond and is a nitrogen, both R 23  and R 24  are absent; 
         wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13  and R 14 , or R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23  and R 24 , K when present, are each independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, halo, cyano, nitro; or two adjacent groups R 3  through R 14 , or groups R 15  through R 24 , together with the atoms to which they are attached on the ring of (IIA) or (IIB) independently form a three to eight member cycloalkane, substituted cycloalkane, cycloalkene, substituted cycloalkene, aryl, substituted aryl, heterocycle with one to three hetero atoms of nitrogen, oxygen or sulfur in the ring, or substituted heterocycle with one to three hetero atoms of nitrogen, oxygen or sulfur in the ring; and when all of the bonds to the ring ammonium nitrogen are saturated, then any of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23  or R 24 , which is attached to the ammonium nitrogen is a straight or branched alkyl group of four carbons or fewer. 
       
     
     
         12 . The method of  claim 11 , wherein transport of a compound of Formula (I) into the central nervous system is facilitated by interaction of the compound with the blood brain barrier choline transporter. 
     
     
         13 . The method of  claim 11 , wherein the compound of Formula (I) binds selectively to one or more subtypes of the nicotinic acetylcholine receptors. 
     
     
         14 . The method of  claim 13 , wherein the selective modulation comprises activation of the function of nicotinic acetylcholine receptors as an agonist or as a partial agonist. 
     
     
         15 . The method of  claim 13 , wherein the selective modulation comprises inactivation of the function of nicotinic acetylcholine receptors as an antagonist. 
     
     
         16 . The method of  claim 13 , wherein there is a decrease in the stimulant-evoked release of a neurotransmitter from a central nervous system tissue. 
     
     
         17 . The method of  claim 13 , wherein there is an increase in the release of a neurotransmitter from a central nervous system tissue. 
     
     
         18 . The method of  claim 16 , wherein the neurotransmitter released is selected from the group consisting of dopamine, norepinephrine, serotonin, gamma-aminobutyric acid, and glutamate. 
     
     
         19 . The method of  claim 17 , wherein the neurotransmitter released is selected from the group consisting of dopamine, norepinephrine, serotonin, gamma-aminobutyric acid, and glutamate. 
     
     
         20 . The method of  claim 11 , wherein the compound of Formula (I) is selected from the group consisting of:
 N,N′-(1,6-hexanediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium diiodide;   N,N′-(1,8-octananediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium diiodide;   N,N′-(1,9-nonanediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium dibromide;   N,N′-(1,10-decanediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium diiodide;   N,N′-(1,1′-undecanediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium dibromide;   N,N′-(1,4-butanediyl)-3,3′-(1,12-dodecanediyl)-bis-pyridinium diiodide;   N,3′-(1,12-dodecanediyl)-3,N′-(1,12-dodecanediyl)-bis-pyridinium dibromide.   
     
     
         21 . A method for preventing and/or treating a central nervous system associated disorder comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein X 1⊖  and X 2⊖  are each independently an organic or inorganic anion; 
         wherein Q and T are each independently attached to R 1  and R 2 , and Q and T are each independently selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic; SOY 1 , SO 2 Y 1 , SO 2 OY 1  or SO 2 NHY 1 , where Y 1  is selected from hydrogen, lower alkyl, alkenyl, alkynyl or aryl, and where Y 1  is not hydrogen in SOY 1  and if Y 1  is alkenyl or alkynyl, the site of unsaturation is not conjugated with a heteroatom; COY 2 , where Y 2  is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aryloxy, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, or substituted heterocyclic, and where if Y 2  comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the carbonyl group; OY 3 , where Y 3  is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, acyl, alkylsulfonyl, arylsulfonyl, heterocyclic, or substituted heterocyclic, where if Y 3  comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the oxygen; NY 4 Y 5 , where Y 4  and Y 5  are each independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, acyl, alkylsulfonyl, arylsulfonyl, heterocyclic, or substituted heterocyclic, where if Y 4  or Y 5  comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the nitrogen; SY 6 , where Y 6  is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, or substituted heterocyclic, and where if Y 6  comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the sulfur; 
         wherein R 1  and R 2  are each independently five or six membered rings as shown in formulas (IIA) and (IIB), wherein each ring of R 1  and R 2  has one, two or three nitrogen atoms, each ring of R 1  and R 2  has one quaternized nitrogen, and two of R 3  through R 24  of each R 1  and two of R 3  through R 24  of each R 2  are replaced by one attachment to Q and one attachment to T; 
       
       
         
           
           
               
               
           
         
         wherein A 1  is carbon or nitrogen, provided that when A 1  joins a ring atom with an unsaturated bond or is a nitrogen, R 3  is absent, and when A 1  joins a ring atom with an unsaturated bond and is a nitrogen, both R 3  and R 4  are absent; 
         wherein A 2  is carbon or nitrogen, provided that when A 2  joins a ring atom with an unsaturated bond or is a nitrogen, R 5  is absent, and when A 2  joins a ring atom with an unsaturated bond and is a nitrogen, both R 5  and R 6  are absent; 
         wherein A 3  is carbon or nitrogen, provided that when A 3  joins a ring atom with an unsaturated bond or is a nitrogen, R 7  is absent, and when A 3  joins a ring atom with an unsaturated bond and is a nitrogen, both R 7  and R 8  are absent; 
         wherein A 4  is carbon or nitrogen, provided that when A 4  joins a ring atom with an unsaturated bond or is a nitrogen, R 9  is absent, and when A 4  joins a ring atom with an unsaturated bond and is a nitrogen, both R 9  and R 10  are absent; 
         wherein A 5  is carbon or nitrogen, provided that when A 5  joins a ring atom with an unsaturated bond or is a nitrogen, R 11  is absent, and when A 5  joins a ring atom with an unsaturated bond and is a nitrogen, both R 11  and R 12  are absent; 
         wherein A 6  is carbon or nitrogen, provided that when A 6  joins a ring atom with an unsaturated bond or is a nitrogen, R 13  is absent, and when A 6  joins a ring atom with an unsaturated bond and is a nitrogen, both R 13  and R 14  are absent; 
         wherein A 7  is carbon or nitrogen, provided that when A 7  joins a ring atom with an unsaturated bond or is a nitrogen, R 15  is absent, and when A 7  joins a ring atom with an unsaturated bond and is a nitrogen, both R 15  and R 16  are absent; 
         wherein A 8  is carbon or nitrogen, provided that when A 8  joins a ring atom with an unsaturated bond or is a nitrogen, R 17  is absent, and when A 8  joins a ring atom with an unsaturated bond and is a nitrogen, both R 17  and R 18  are absent; 
         wherein A 9  is carbon or nitrogen, provided that when A 9  joins a ring atom with an unsaturated bond or is a nitrogen, R 19  is absent, and when A 9  joins a ring atom with an unsaturated bond and is a nitrogen, both R 19  and R 20  are absent; 
         wherein A 10  is carbon or nitrogen, provided that when A 10  joins a ring atom with an unsaturated bond or is a nitrogen, R 21  is absent, and when A 10  joins a ring atom with an unsaturated bond and is a nitrogen, both R 21  and R 22  are absent; 
         wherein A 11  is carbon or nitrogen, provided that when A 11  joins a ring atom with an unsaturated bond or is a nitrogen, R 23  is absent, and when A 11  joins a ring atom with an unsaturated bond and is a nitrogen, both R 23  and R 24  are absent; 
         wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13  and R 14 , or R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23  and R 24 , K when present, are each independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, halo, cyano, nitro; or two adjacent groups R 3  through R 14 , or groups R 15  through R 24 , together with the atoms to which they are attached on the ring of (IIA) or (IIB) independently form a three to eight member cycloalkane, substituted cycloalkane, cycloalkene, substituted cycloalkene, aryl, substituted aryl, heterocycle with one to three hetero atoms of nitrogen, oxygen or sulfur in the ring, or substituted heterocycle with one to three hetero atoms of nitrogen, oxygen or sulfur in the ring; and when all of the bonds to the ring ammonium nitrogen are saturated, then any of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23  or R 24  which is attached to the ammonium nitrogen is a straight or branched alkyl group of four carbons or fewer. 
       
     
     
         22 . The method of  claim 21 , wherein transport of a compound of Formula (I) into the central nervous system is facilitated by interaction of the compound with the blood brain barrier choline transporter. 
     
     
         23 . The method of  claim 21 , wherein the central nervous system associated disorder is selected from the group consisting of Alzheimer's disease, dementia, cognitive dysfunctions, attention deficit disorders, affective disorders, extrapyramidal motor function disorders, Parkinson's disease, progressive supramolecular palsy, Huntington's disease, Gilles de la Tourette syndrome, tardive dyskinesia, neuroendocrine disorders, dysregulation of food intake, disorders of nociception, pain, mood and emotional disorders, depression, panic anxiety, psychosis, schizophrenia, and epilepsy. 
     
     
         24 . The method of  claim 21 , wherein the compound of Formula (I) binds selectively to one or more subtypes of the nicotinic acetylcholine receptors. 
     
     
         25 . The method of  claim 24 , wherein administering the compound of Formula (I) activates the function of the nicotinic acetylcholine receptors as an agonist or as a partial agonist. 
     
     
         26 . The method of  claim 24 , wherein administering the compound of Formula (I) inactivates the function of the nicotinic acetylcholine receptors as an antagonist. 
     
     
         27 . The method of  claim 24 , wherein there is a decrease in the stimulant-evoked release of a neurotransmitter from a central nervous system tissue. 
     
     
         28 . The method of  claim 24 , wherein there is an increase in the release of a neurotransmitter from a central nervous system tissue. 
     
     
         29 . The method of  claim 27 , wherein the neurotransmitter is selected from the group consisting of dopamine, norepinephrine, serotonin, gamma-aminobutyric acid, and glutamate. 
     
     
         30 . The method of  claim 28 , wherein the neurotransmitter is selected from the group consisting of dopamine, norepinephrine, serotonin, gamma-aminobutyric acid, and glutamate. 
     
     
         31 . The method of  claim 21 , wherein the compound of Formula (I) is selected from the group consisting of:
 N,N′-(1,6-hexanediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium diiodide;   N,N′-(1,8-octananediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium diiodide;   N,N′-(1,9-nonanediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium dibromide;   N,N′-(1,10-decanediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium diiodide;   N,N′-(1,1′-undecanediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium dibromide;   N,N′-(1,4-butanediyl)-3,3′-(1,12-dodecanediyl)-bis-pyridinium diiodide;   N,3′-(1,12-dodecanediyl)-3,N′-(1,12-dodecanediyl)-bis-pyridinium dibromide.   
     
     
         32 . A method for preventing and/or treating substance use and/or abuse comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein X 1⊖  and X 2⊖  are each independently an organic or inorganic anion; 
         wherein Q and T are each independently attached to R 1  and R 2 , and Q and T are each independently selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic; SOY 1 , SO 2 Y 1 , SO 2 OY 1  or SO 2 NHY 1 , where Y 1  is selected from hydrogen, lower alkyl, alkenyl, alkynyl or aryl, and where Y 1  is not hydrogen in SOY 1  and if Y 1  is alkenyl or alkynyl, the site of unsaturation is not conjugated with a heteroatom; COY 2 , where Y 2  is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aryloxy, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, or substituted heterocyclic, and where if Y 2  comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the carbonyl group; OY 3 , where Y 3  is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, acyl, alkylsulfonyl, arylsulfonyl, heterocyclic, or substituted heterocyclic, where if Y 3  comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the oxygen; NY 4 Y 5 , where Y 4  and Y 5  are each independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, acyl, alkylsulfonyl, arylsulfonyl, heterocyclic, or substituted heterocyclic, where if Y 4  or Y 5  comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the nitrogen; SY 6 , where Y 6  is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, or substituted heterocyclic, and where if Y 6  comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the sulfur; 
         wherein R 1  and R 2  are each independently five or six membered rings as shown in formulas (IIA) and (IIB), wherein each ring of R 1  and R 2  has one, two or three nitrogen atoms, each ring of R 1  and R 2  has one quaternized nitrogen, and two of R 3  through R 24  of each R 1  and two of R 3  through R 24  of each R 2  are replaced by one attachment to Q and one attachment to T; 
       
       
         
           
           
               
               
           
         
         wherein A 1  is carbon or nitrogen, provided that when A 1  joins a ring atom with an unsaturated bond or is a nitrogen, R 3  is absent, and when A 1  joins a ring atom with an unsaturated bond and is a nitrogen, both R 3  and R 4  are absent; 
         wherein A 2  is carbon or nitrogen, provided that when A 2  joins a ring atom with an unsaturated bond or is a nitrogen, R 5  is absent, and when A 2  joins a ring atom with an unsaturated bond and is a nitrogen, both R 5  and R 6  are absent; 
         wherein A 3  is carbon or nitrogen, provided that when A 3  joins a ring atom with an unsaturated bond or is a nitrogen, R 7  is absent, and when A 3  joins a ring atom with an unsaturated bond and is a nitrogen, both R 7  and R 8  are absent; 
         wherein A 4  is carbon or nitrogen, provided that when A 4  joins a ring atom with an unsaturated bond or is a nitrogen, R 9  is absent, and when A 4  joins a ring atom with an unsaturated bond and is a nitrogen, both R 9  and R 10  are absent; 
         wherein A 5  is carbon or nitrogen, provided that when A 5  joins a ring atom with an unsaturated bond or is a nitrogen, R 11  is absent, and when A 5  joins a ring atom with an unsaturated bond and is a nitrogen, both R 11  and R 12  are absent; 
         wherein A 6  is carbon or nitrogen, provided that when A 6  joins a ring atom with an unsaturated bond or is a nitrogen, R 13  is absent, and when A 6  joins a ring atom with an unsaturated bond and is a nitrogen, both R 13  and R 14  are absent; 
         wherein A 7  is carbon or nitrogen, provided that when A 7  joins a ring atom with an unsaturated bond or is a nitrogen, R 15  is absent, and when A 7  joins a ring atom with an unsaturated bond and is a nitrogen, both R 15  and R 16  are absent; 
         wherein A 8  is carbon or nitrogen, provided that when A 8  joins a ring atom with an unsaturated bond or is a nitrogen, R 17  is absent, and when A 8  joins a ring atom with an unsaturated bond and is a nitrogen, both R 17  and R 18  are absent; 
         wherein A 9  is carbon or nitrogen, provided that when A 9  joins a ring atom with an unsaturated bond or is a nitrogen, R 19  is absent, and when A 9  joins a ring atom with an unsaturated bond and is a nitrogen, both R 19  and R 20  are absent; 
         wherein A 10  is carbon or nitrogen, provided that when A 10  joins a ring atom with an unsaturated bond or is a nitrogen, R 21  is absent, and when A 10  joins a ring atom with an unsaturated bond and is a nitrogen, both R 21  and R 22  are absent; 
         wherein A 11  is carbon or nitrogen, provided that when A 11  joins a ring atom with an unsaturated bond or is a nitrogen, R 23  is absent, and when A 11  joins a ring atom with an unsaturated bond and is a nitrogen, both R 23  and R 24  are absent; 
         wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13  and R 14 , or R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23  and R 24 , when present, are each independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, halo, cyano, nitro; or two adjacent groups R 3  through R 14 , or groups R 15  through R 24 , together with the atoms to which they are attached on the ring of (IIA) or (IIB) independently form a three to eight member cycloalkane, substituted cycloalkane, cycloalkene, substituted cycloalkene, aryl, substituted aryl, heterocycle with one to three hetero atoms of nitrogen, oxygen or sulfur in the ring, or substituted heterocycle with one to three hetero atoms of nitrogen, oxygen or sulfur in the ring; and when all of the bonds to the ring ammonium nitrogen are saturated, then any of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23  or R 24  which is attached to the ammonium nitrogen is a straight or branched alkyl group of four carbons or fewer. 
       
     
     
         33 . The method of  claim 32 , wherein transport of a compound of Formula (I) into the central nervous system is facilitated by interaction of the compound with the blood brain barrier choline transporter. 
     
     
         34 . The method of  claim 32  wherein the substance use/abuse is selected from the group consisting of nicotine abuse, nicotine intoxication, amphetamine abuse, methamphetamine abuse, MDMA abuse, methylphenidate abuse, cocaine abuse, and alcohol abuse. 
     
     
         35 . The method of  claim 32 , wherein the compound of Formula (I) binds selectively to one or more subtypes of the nicotinic acetylcholine receptors. 
     
     
         36 . The method of  claim 35 , wherein the selective modulation comprises activation of the function of nicotinic acetylcholine receptors as an agonist or as a partial agonist. 
     
     
         37 . The method of  claim 35 , wherein the selective modulation comprises inactivation of the function of nicotinic acetylcholine receptors as an antagonist. 
     
     
         38 . The method of  claim 35 , wherein there is a decrease in the stimulant-evoked release of a neurotransmitter from a central nervous system tissue. 
     
     
         39 . The method of  claim 35 , wherein there is an increase in the release of a neurotransmitter from a central nervous system tissue. 
     
     
         40 . The method of  claim 38 , wherein the neurotransmitter released is selected from the group consisting of dopamine, norepinephrine, serotonin, gamma-aminobutyric acid, and glutamate. 
     
     
         41 . The method of  claim 39 , wherein the neurotransmitter released is selected from the group consisting of dopamine, norepinephrine, serotonin, gamma-aminobutyric acid, and glutamate. 
     
     
         42 . The method of  claim 32 , wherein the compound of Formula (I) is selected from the group consisting of:
 N,N′-(1,6-hexanediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium diiodide;   N,N′-(1,8-octananediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium diiodide;   N,N′-(1,9-nonanediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium dibromide;   N,N′-(1,10-decanediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium diiodide;   N,N′-(1,1′-undecanediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium dibromide;   N,N′-(1,4-butanediyl)-3,3′-(1,12-dodecanediyl)-bis-pyridinium diiodide;   N,3′-(1,12-dodecanediyl)-3,N′-(1,12-dodecanediyl)-bis-pyridinium dibromide.   
     
     
         43 . A method for preventing and/or treating gastrointestinal tract disorders comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein X 1⊖  and X 2⊖  are each independently an organic or inorganic anion; 
         wherein Q and T are each independently attached to R 1  and R 2 , and Q and T are each independently selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic; SOY 1 , SO 2 Y 1 , SO 2 OY 1  or SO 2 NHY 1 , where Y 1  is selected from hydrogen, lower alkyl, alkenyl, alkynyl or aryl, and where Y 1  is not hydrogen in SOY 1  and if Y 1  is alkenyl or alkynyl, the site of unsaturation is not conjugated with a heteroatom; COY 2 , where Y 2  is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aryloxy, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, or substituted heterocyclic, and where if Y 2  comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the carbonyl group; OY 3 , where Y 3  is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, acyl, alkylsulfonyl, arylsulfonyl, heterocyclic, or substituted heterocyclic, where if Y 3  comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the oxygen; NY 4 Y 5 , where Y 4  and Y 5  are each independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, acyl, alkylsulfonyl, arylsulfonyl, heterocyclic, or substituted heterocyclic, where if Y 4  or Y 5  comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the nitrogen; SY 6 , where Y 6  is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, or substituted heterocyclic, and where if Y 6  comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the sulfur; 
         wherein R 1  and R 2  are each independently five or six membered rings as shown in formulas (IIA) and (IIB), wherein each ring of R 1  and R 2  has one, two or three nitrogen atoms, each ring of R 1  and R 2  has one quaternized nitrogen, and two of R 3  through R 24  of each R 1  and two of R 3  through R 24  of each R 2  are replaced by one attachment to Q and one attachment to T; 
       
       
         
           
           
               
               
           
         
         wherein A 1  is carbon or nitrogen, provided that when A 1  joins a ring atom with an unsaturated bond or is a nitrogen, R 3  is absent, and when A 1  joins a ring atom with an unsaturated bond and is a nitrogen, both R 3  and R 4  are absent; 
         wherein A 2  is carbon or nitrogen, provided that when A 2  joins a ring atom with an unsaturated bond or is a nitrogen, R 5  is absent, and when A 2  joins a ring atom with an unsaturated bond and is a nitrogen, both R 5  and R 6  are absent; 
         wherein A 3  is carbon or nitrogen, provided that when A 3  joins a ring atom with an unsaturated bond or is a nitrogen, R 7  is absent, and when A 3  joins a ring atom with an unsaturated bond and is a nitrogen, both R 7  and R 8  are absent; 
         wherein A 4  is carbon or nitrogen, provided that when A 4  joins a ring atom with an unsaturated bond or is a nitrogen, R 9  is absent, and when A 4  joins a ring atom with an unsaturated bond and is a nitrogen, both R 9  and R 10  are absent; 
         wherein A 5  is carbon or nitrogen, provided that when A 5  joins a ring atom with an unsaturated bond or is a nitrogen, R 11  is absent, and when A 5  joins a ring atom with an unsaturated bond and is a nitrogen, both R 11  and R 12  are absent; 
         wherein A 6  is carbon or nitrogen, provided that when A 6  joins a ring atom with an unsaturated bond or is a nitrogen, R 13  is absent, and when A 6  joins a ring atom with an unsaturated bond and is a nitrogen, both R 13  and R 14  are absent; 
         wherein A 7  is carbon or nitrogen, provided that when A 7  joins a ring atom with an unsaturated bond or is a nitrogen, R 15  is absent, and when A 7  joins a ring atom with an unsaturated bond and is a nitrogen, both R 15  and R 16  are absent; 
         wherein A 8  is carbon or nitrogen, provided that when A 8  joins a ring atom with an unsaturated bond or is a nitrogen, R 17  is absent, and when A 8  joins a ring atom with an unsaturated bond and is a nitrogen, both R 17  and R 18  are absent; 
         wherein A 9  is carbon or nitrogen, provided that when A 9  joins a ring atom with an unsaturated bond or is a nitrogen, R 19  is absent, and when A 9  joins a ring atom with an unsaturated bond and is a nitrogen, both R 19  and R 20  are absent; 
         wherein A 10  is carbon or nitrogen, provided that when A 10  joins a ring atom with an unsaturated bond or is a nitrogen, R 21  is absent, and when A 10  joins a ring atom with an unsaturated bond and is a nitrogen, both R 21  and R 22  are absent; 
         wherein A 11  is carbon or nitrogen, provided that when A 11  joins a ring atom with an unsaturated bond or is a nitrogen, R 23  is absent, and when A 11  joins a ring atom with an unsaturated bond and is a nitrogen, both R 23  and R 24  are absent; 
         wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13  and R 14 , or R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23  and R 24 , when present, are each independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, halo, cyano, nitro; or two adjacent groups R 3  through R 14 , or groups R 15  through R 24 , together with the atoms to which they are attached on the ring of (IIA) or (IIB) independently form a three to eight member cycloalkane, substituted cycloalkane, cycloalkene, substituted cycloalkene, aryl, substituted aryl, heterocycle with one to three hetero atoms of nitrogen, oxygen or sulfur in the ring, or substituted heterocycle with one to three hetero atoms of nitrogen, oxygen or sulfur in the ring; and when all of the bonds to the ring ammonium nitrogen are saturated, then any of R 3 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23  or R 24  which is attached to the ammonium nitrogen is a straight or branched alkyl group of four carbons or fewer. 
       
     
     
         44 . The method of  claim 43  wherein the gastrointestinal tract disorder is selected from the group consisting of irritable bowel syndrome, colitis, diarrhea, constipation, gastric acid secretion, and ulcers. 
     
     
         45 . The method of  claim 43 , wherein the compound of Formula (I) binds selectively to one or more subtypes of the nicotinic acetylcholine receptors. 
     
     
         46 . The method of  claim 45 , wherein the selective modulation comprises activation of the function of nicotinic acetylcholine receptors as an agonist or as a partial agonist. 
     
     
         47 . The method of  claim 45 , wherein the selective modulation comprises inactivation of the function of nicotinic acetylcholine receptors as an antagonist. 
     
     
         48 . The method of  claim 45 , wherein there is a decrease in the stimulant-evoked release of a neurotransmitter from a central nervous system tissue. 
     
     
         49 . The method of  claim 45 , wherein there is an increase in the release of a neurotransmitter from a central nervous system tissue. 
     
     
         50 . The method of  claim 48 , wherein the neurotransmitter released is selected from the group consisting of dopamine, norepinephrine, serotonin, gamma-aminobutyric acid, and glutamate. 
     
     
         51 . The method of  claim 49 , wherein the neurotransmitter released is selected from the group consisting of dopamine, norepinephrine, serotonin, gamma-aminobutyric acid, and glutamate. 
     
     
         52 . The method of  claim 43 , wherein the compound of Formula (I) is selected from the group consisting of:
 N,N′-(1,6-hexanediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium diiodide;   N,N′-(1,8-octananediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium diiodide;   N,N′-(1,9-nonanediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium dibromide;   N,N′-(1,10-decanediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium diiodide;   N,N′-(1,1′-undecanediyl)-3,3′-(1,9-decanediyn-1,10-diyl)-bis-pyridinium dibromide;   N,N′-(1,4-butanediyl)-3,3′-(1,12-dodecanediyl)-bis-pyridinium diiodide;   N,3′-(1,12-dodecanediyl)-3,N′-(1,12-dodecanediyl)-bis-pyridinium dibromide.