Compositions and methods of treatment of sympathetically maintained pain

Abstract

Sympathetically maintained pain is treated topically by administering to the site where sympathetically maintained pain is present an α-1-adrenergic antagonist, α-2-adrenergic agonist, or other drug that depletes or blocks synthesis of sympathetic norepinephrine, known collectively as sympatholytic agents. Chemical formulas for several sympatholytic agents are given.

1. A method of treating sympathetically maintained pain in peripheral tissues comprising topically administering to a patient having sympathetically maintained pain at a peripheral site where the pain originates, wherein the sympathetically maintained pain can be diagnosed by local anesthetic blockade of the appropriate sympathetic ganglion or adrenergic blockade via intravenous administration of phentolamine, and rekindled by intradermal injection of norepinephrine, an effective amount of a compound other than guanethidine or clonidine that depletes norepinephrine or blocks synthesis or release of norepinephrine at the sympathetic terminals in a pharmaceutically acceptable carrier for topical application selected from the group consisting of a lotion, ointment, solution, and transdermal patch to cause measurable relief from the sympathetically maintained pain. 
     
     
       2. The method of  claim 1  wherein the compound is administered in a transdermal patch. 
     
     
       3. The method of  claim 1  wherein the compound is selected from the group consisting of bethanidine, guanclofine, guanoxan, guanazodine, guanoxyfen, guanocline, guanoctine, and guanadrel. 
     
     
       4. The method of  claim 1  wherein the compound is selected from the group consisting of guanoxabenz, and guanoclor. 
     
     
       5. The method of  claim 1  wherein the compound is selected from the group consisting of debrisoquin and guanisoquin. 
     
     
       6. The method of  claim 1  wherein the compound is selected from the group consisting of solypertine, naftopidil, saterinone, trazodone, nefazodone, tiospirone, 3-[2-[4-(o-methoxyphenyl)-1-piperazinyl]ethyl]-2,4(1H,3H)quinazolinedione monohydrochloride, and 1-[2-ethoxy-2-(3′-pyridyl)ethyl]-4-(2′-methoxy-phenyl)piperazine. 
     
     
       7. The method of  claim 1  wherein the compound is a Rauwolfia alkaloid. 
     
     
       8. The method of  claim 1  wherein the compound is an ergot alkaloid. 
     
     
       9. The method of  claim 1  wherein the compound is the compound 5-n-butylpicolinic acid hydrazide. 
     
     
       10. The method of  claim 1  wherein the compound is selected from the group consisting of 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline and 1-(2-mercaptacetyl)-L-proline. 
     
     
       11. The method of  claim 1  wherein the compound is bretylium. 
     
     
       12. The method of  claim 1  wherein the compound is methylapogalanthamine. 
     
     
       13. A method of treating sympathetically maintained pain in peripheral tissues comprising topically administering to a patient a compound other than guanethidine or clonidine effective to treat peripheral sympathetically maintained pain at the site of treatment by blocking the effect of norepinephrine on nociceptor terminals, without systemic side effects of postural hypotension, headache, tachycardia, or nasal stuffiness.  
     
     
       14. The method of  claim 13  wherein the compound is a sympatholytic agent.  
     
     
       15. The method of  claim 13  wherein the compound has the structure represented by Formula I: 
                   
       
         wherein A is selected from the group consisting of aryl, aryloxy, anilino, arylamino, diarylamino, heteroaryl, heteroaryloxy, and heteroarylamino, which may be substituted with one or more radicals selected from the group consisting of alkyl, branched alkyl, cycloalkyl, hydroxyl, alkoxy, cycloalkylalkyl, alkoxyalkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyano, oxo, halogen, thioalkyl, dialkylamino, arylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; B is independently selected from the group consisting of linear alkylene containing from  1  to  4  methylene units, branched alkylene, imino, and thio; and n is either  2  or  3 ; or a pharmaceutically acceptable salt thereof.  
       
     
     
       16. The method of  claim 15  wherein A is selected from the group consisting of phenyl, substituted phenyl, phenoxy, substituted phenoxy, naphthyl, tetrahydronaphthyl, and diarylamino; B is methylene or  1 - ethylene; and n is  2 .    
     
     
       17. The method of  claim 15  wherein A is substituted phenyl, in which positions  2  and  6  of the phenyl ring are substituted by radicals independently selected from the group consisting of hydrido, chloro, methyl, ethyl, cyclopropyl, and thiomethyl and positions  3 ,  4 , and  5  are substituted by radicals independently selected from the group consisting of hydrido,  2 - propyl, tertbutyl, hydroxyl, trifluoromethyl, chloro, and fluoro; B is methylene or  1   - ethylene when A is substituted phenoxy; and n is  2 .    
     
     
       18. The method of  claim 15  wherein A is diarylamino, in which case each aryl group is optionally independently substituted by hydroxyl; B is methylene; and n is  2 .  
     
     
       19. The method of  claim 15  wherein A is  1 - naphthyl or tetrahydronaphthyl; B is either zero or one methylene unit; and n is  2 .    
     
     
       20. The method of  claim 15  wherein the compound is selected from the group consisting of tetrahydrozoline, naphazoline, phentolamine, dexlofexidine, oxymetazoline, cirazoline, xylometazoline, and tolazidine.  
     
     
       21. The method of  claim 13  wherein the compound has the structure represented by Formula II: 
                   
       
         wherein A 
         2  
         is selected from the group consisting of alkyl, branched alkyl, aryl, aryloxy, heteroaryl, and heterocyclyl, which is optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, aryl, alkoxy, hydroxyl, amino, alkylamino, arylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl or arylsulfonyl; R 
         1  
         and R 
         2  
         are independently selected from the group consisting of hydrido, lower alkyl, hydroxyl and cyano; R 
         3  
         and R 
         4  
         are independently selected from the group consisting of hydrido and lower alkyl, or together form a carbonyl moiety; R 
         5  
         is selected from the group consisting of hydrido and lower alkyl; and n is any value between  0  and  4  inclusive; or a pharmaceutically acceptable salt thereof.  
       
     
     
       22. The method of  claim 21  wherein A 2    is selected from the group consisting of lower alkyl, phenyl, substituted phenyl, phenoxy, substituted phenoxy, anilino, substituted anilino, azacyclic, benzodioxan, and substituted dioxolane; R   1    is selected from the group consisting of hydrido, methyl, and hydroxyl, R   2    is selected from the group consisting of hydrido and cyano; R   3    and R   4    are independently selected from the group consisting of hydrido or methyl, or together form a carbonyl; R   5    is hydrogen; and n is any value from  0  to  3  inclusive.    
     
     
       23. The method of  claim 21  wherein A 2    is selected from the group consisting of lower alkyl,  2 , 6   - dichlorophenyl, phenoxy,  (   2 , 6   - dichloro ) phenoxy,  (   2 , 6   -dichloro) anilino,  4   - phenyl -   1 , 2 , 3 , 6   - tetrahydropyridinyl, octahydro -   1   - azocinyl, octahydro -   2   - azocinyl, benzodioxan -   2   - yl, and  1 , 4   - dioxaspiro[ 4 , 5 ]dec -   2   - yl; R   1    is selected from the group consisting of hydrido, methyl, and hydroxyl, R   2    is selected from the group consisting of hydrido and cyano; R   3    and R   4    are independently selected from the group consisting of hydrido and methyl, or together form a carbonyl; R   5    is hydrogen; and n is any value from  0  to  3  inclusive.    
     
     
       24. The method of  claim 21  wherein the compound is selected from the group consisting of bethanidine, guanfacine, guanclofine, guanoxan, guanazodine, guanoxyfen, guanocline, guanoctine, and guanadrel.  
     
     
       25. The method of  claim 13  wherein the compound has the structure represented by Formula III: 
                   
       
         wherein A 
         3  
         is selected from the group consisting of alkyl, branched alkyl, aryl, aryloxy, heteroaryl, and heterocyclic moiety, which optionally are substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, aryl, alkoxy, hydroxyl, amino, alkylamino, arylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; B 
         2  
         is carbon, wherein it forms an unsaturated imino linkage with the adjacent nitrogen, or linear or branched alkylene moiety of  1 - 4  methylene units in length; R 
         1  
         and R 
         2  
         are as defined for Formula II; and R 
         6  
         is selected from the group consisting of hydrogen and lower alkyl, when the attached nitrogen is not incorporated into an unsaturated imino bond; or a pharmaceutically acceptable salt thereof.  
       
     
     
       26. The method of  claim 25  wherein A 3    is selected from the group consisting of phenyl and substituted phenyl; B   2    is a carbon attached by a double bond to the adjacent nitrogen to form an imino moiety, or B   2    is a saturated linear alkyl chain of  2  methylene units; and R   1   , R   2   , and R   6    are hydrogen.    
     
     
       27. The method of  claim 25  wherein A 3    is a  2 , 6   - disubstituted phenyl moiety, wherein the substituents are selected from the group consisting of chloro and methyl.    
     
     
       28. The method of  claim 25  wherein the compound is selected from the group consisting of guanabenz, guanoxabenz, and guanoclor.  
     
     
       29. The method of  claim 13  wherein the compound has the structure of Formula IV: 
                   
         wherein A   4    is selected from the group consisting of aryl and heteroaryl, which is optionally substituted by one or more radicals selected from the group consisting of alkyl, branched alkyl, cycloalkyl, hydroxyl, alkoxy, cycloalkylalkyl, alkoxyalkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyano, halogen, thioalkyl, dialkylamino, arylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; X is selected from the group consisting of thio, imino, and methylene; R   7    is selected from the group consisting of hydrogen, lower alkyl, and oxygen - containing heterocycle; and n is either  2  or  3 ; or a pharmaceutically acceptable salt thereof.    
     
     
       30. The method of  claim 29  wherein A 4    is selected from the group consisting of phenyl; substituted phenyl, on which positions  2  and  6  of the phenyl ring are independently substituted by a radical selected from the group consisting of hydrogen, chloro, methyl, ethyl, and cycloalkyl, and positions  3 ,  4 , and  5  are independently substituted by a radical selected from the group consisting of hydrogen, methyl, trifluoromethyl, fluoro, and cyano;  3   - thienyl, on which positions  2  and  4  are independently substituted by a radical selected from the group consisting of hydrogen, chloro, methyl, ethyl, and cycloalkyl;  1   - naphthyl;  5 , 6 , 7 , 8   - tetrahydronaphthyl -   1   - yl; pyrrolyl; oxazolyl; isoxazolyl; indol -   3   - yl; indazol -   3   - yl; quinolinyl; quinazolinyl; quinoxazolinyl; benzoxazolyl; benzothiophen -   3   - yl; and pyrimidin -   4   - yl, on which positions  3  and  5  are independently substituted by hydrogen, chloro, methyl, ethyl, cycloalkyl, or methoxy; R   7    is hydrogen or tetrahydropyran -   2   - yl; X is thio or imino; and n is  2 .    
     
     
       31. The method of  claim 29  wherein A 4    is selected from the group consisting of phenyl,  2 , 6   - dichlorophenyl,  2 , 6   - dimethylphenyl,  2 , 6   - diethylphenyl,  3 , 4   - dihydroxyphenyl,  3   - fluoro -   6   - methylphenyl,  2   - chloro -   5   - trifluoromethylphenyl,  2   - chloro -   4   - methylphenyl,  3   - chloro -   4   - methylthien -   3   - yl,  5 , 6 , 7 , 8   - tetrahydronaphth -   1   - yl, and  4   - chloro -   5   - methoxy -   2   - methylpyrimidin -   4   - yl; R   7    is hydrogen or tetrahydropyran -   2   - yl; X is thio or imino; and n is  2 .    
     
     
       32. The method of  claim 29  wherein the compound is selected from the group consisting of xylazine, flutonidine, moxonidine, tramazoline, tolonidine, piclonidine, and tiamenidine.  
     
     
       33. The method of  claim 13  wherein the compound has the structure of Formula V: 
                   
         wherein Y represents the remainder of a cyclic structure selected from the group consisting of  1 , 2 , 3 , 4   - tetrahydroisoquinoline and  2 , 3   - dihydroisoindole, which is optionally substituted by one or more radicals selected from the group consisting of halogen, lower alkyl, alkoxy, hydroxyl, oxo, amino, dialkylamino, aryl, aryloxy, cyano, alkoxycarbonyl, aminocarbonyl, alkylsulfinyl, alkylsulfonyl, alkanoyl, and alkylthio; and R   1    and R   2    are defined as in Formula II; or a pharmaceutically acceptable salt thereof.    
     
     
       34. The method of  claim 33  wherein Y is substituted tetrahydroisoquinoline, the substituents are either hydrogen or halogen on position  7  of the tetrahydroisoquinoline nucleus, and R 1    and R   2    are both hydrogen.    
     
     
       35. The method of  claim 33  wherein the compound is selected from the group consisting of debrisoquin and guanisoquin.  
     
     
       36. The method of  claim 13  wherein the compound has the structure of Formula VI: 
                   
       
         or Formula VII:  
         
           
           
               
               
           
         
       
       
         wherein R 
         8  
         is selected from the group consisting of hydrogen, alkyl, and cycloalkyl; R 
         9  
         and R 
         10  
         are independently selected from the group consisting of hydrogen, alkyl, alkoxy, acyloxy, dialkylamino, and alkylthio; R 
         11  
         is selected from the group consisting of hydrogen, alkyl, and alkoxy; R 
         12  
         and R 
         13  
         are independently selected from the group consisting of hydrogen and alkyl; n, n′ and n″ are independently  2  to  4  inclusive; and Z is selected from the group consisting of alkyl, alkoxy, alkylaryl, alkenylaryl, alkoxyalkyl, hydroxyalkyl, aryl, heteroaryl, and heteroalkyl; or a pharmaceutically acceptable salt thereof.  
       
     
     
       37. The method of  claim 36  wherein the compound is a compound of Formula VI wherein R 8    is hydrogen, R   9    and R   10    are alkoxy; R   11    is selected from the group consisting of hydrogen and alkoxy; and R   12    is selected from the group consisting of hydrogen and alkyl.    
     
     
       38. The method of  claim 36  wherein the c compound is a compound of Formula VII wherein R 8    is hydrogen, R   9    and R   10    are alkoxy; R   11    is selected from the group consisting of hydrogen and alkoxy; and n′ and n″ are independently either  2  or  3 .    
     
     
       39. The method of  claim 36  wherein the compound is a compound of Formula VI, wherein R 9    and R   10    are methoxy; R   11    is selected from the group consisting of hydrogen and methoxy; R   12    is selected from the group consisting of hydrogen and methyl; R   13    is hydrogen; and Z is selected from the group consisting of ethyl, propyl, butyl,  2   - methylpropyl,  1   - methoxyethyl,  2   -(   2   - furoyl )- ethenyl,  2   - tetrahydrofuranoyl,  2   - furoyl,  2   - hydroxy-     2   - methylpropyloxy,  2   - hydroxypropyl, and  2   - thiomethyl-     1 , 3 , 4   - oxadiozol -   4   - yl.    
     
     
       40. The method of  claim 36  wherein the compound is a compound of Formula VII, wherein R 9    and R   10    are methoxy; R   11    is selected from the group consisting of hydrogen and methoxy; Z is selected from the group consisting of ethyl, propyl, butyl,  2   - methylpropyl,  1   - methoxyethyl,  2   -(   2   - furoyl )- ethenyl,  2   - tetrahydrofuranoyl,  2   - furoyl,  2   - hydroxy -   2   - methylpropyloxy,  2   - hydroxypropyl, and  2   - thiomethyl -   1 , 3 , 4   - oxadiazol -   4   - yl; and n′ is  2  and n″ is  2  or  3 .    
     
     
       41. The method of  claim 36  wherein the compound is selected from the group consisting of alfuzosin, bunazosin, doxazosin, metazosin, neldazosin, prazosin, terazosin, trimazosin, tiodazosin, and MY-   5561 .    
     
     
       42. The method of  claim 13  wherein the compound has the structure of Formula VIII: 
                   
       
         wherein N is selected from the group consisting of aryl and heteroaryl, which is optionally substituted with one or more radicals selected from the group consisting of alkyl, branched alkyl, cycloalkyl, hydroxyl, alkoxy, cycloalkylalkyl, alkoxyalkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyano, halogen, thioalkyl, dialkylamino, arylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; and M is defined as:  
         
           
           
               
               
           
         
       
       
         or  
         
           
           
               
               
           
         
       
       
         wherein R 
         14  
         and R 
         15  
         are independently selected from the group consisting of hydrogen, alkyl, alkoxy, and hydroxy; P is selected from the group consisting of heteroaromatic and polycyclic heteroaromatic, which is optionally substituted with one or more radicals selected from the group consisting of halogen, alkyl alkoxy, oxo, cyano, alkoxycarbonyl, arylalkyl, trifluromethyl, and aryloxyalkyl; and Q is selected from the group consisting of oxygen and imino; or a pharmaceutically acceptable salt thereof.  
       
     
     
       43. The method of  claim 42  wherein N is selected from the group consisting of phenyl, pyridyl, thienopyridinyl, indolyl, and pyrimidin-   2   - yl; wherein, if N is phenyl, then the phenyl ring is optionally substituted with one or more radicals selected from the group consisting of: chloro, methoxy, cyano, thiomethyl, and trifluoromethyl; R   14    is selected from the group consisting of hydroxy, ethoxy, and methoxy; R   15    is hydrogen; and P is selected from the group consisting of  3   - pyridyl,  1   - naphthyl,  2   - quinazolin -   1 , 3   - dione,  6 , 7   - methylenedioxyindol -   2   - yl,  1 , 3   - pyrimidin -   2 , 4   - dion -   6   - yl;  3 H -   1 , 2 , 4   - triazol -   3   - on -   2   - yl; and  1 , 2 , 4   - triazolo[ 4 , 3   - a]pyridin -   3   (   2 H )- on -   2   - yl.    
     
     
       44. The method of  claim 42  wherein N is selected from the group consisting of phenyl,  3 - chlorophenyl,  2   - methoxyphenyl,  3   - methoxyphenyl,  3   - trifluoromethylphenyl, and  3   - indolyl.    
     
     
       45. The method of  claim 42  wherein the compound is selected from the group consisting of urapidil, solypertine, naftopidil, saterinone, trazodone, nefazodone, tiospirone, SGB-   15343   -[   2   -[   4   -( o - methoxyphenyl )-   1   - piperazinyl]ethyl] -   2 , 4   (   1 H, 3 H - quinazoli nedione monohydrochloride ) , and IP -   661   -[   2   - ethoxy -   2   - (     3   ′- pyridyl ) ethyl ]-   4   -(   2   ′- methoxy - phenyl ) piperazine.  
     
     
       46. The method of  claim 13  wherein the compound has the structure of Formula IX: 
                   
       
         wherein A 
         5  
         is selected from the group consisting of aryl, aryloxy, arylalkyloxy, arylamino, cycloalkyl, cycloalkyloxy, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroaryloxy, heteroarylamino, and heteroarylsulfonyl, which are optionally substituted with one or more radicals selected from the group consisting of alkyl, branched alkyl, cycloalkyl, hydroxyl, alkoxy, cycloalkylalkyl, alkoxyalkyl, aryl, alkanoyl alkoxycarbonyl, carboxyl, amino, cyano, oxo, halogen, thioalkyl, dialkylamino, heterocyclic, arylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, and arylsulfonyl; K is selected from the group consisting of linear alkylene of  0  to  6  methylene units in length, branched alkylene, alkenyl, cycloalkyl, and arylalkyl; R 
         16  
         and R 
         17  
         are independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, heteroaryl, arylcarbonyl, arylamino, arylcarbonylamino, arylsulfonylamino, carboxylate, aryloxycarbonyl, and heteroarylcarbonyl; R 
         16  
         and R 
         17  
         together represent a double bond linked to an adjacent substituted carbon; or R 
         16  
         and R 
         17  
         represent a spirocyclic ring juncture forming an alicyclic or heterocyclic ring; R 
         18  
         is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, arylamino, and arylcarbonylamino; and n′″ represents a value of  1  to  3 ; or a pharmaceutically acceptable salt thereof.  
       
     
     
       47. The method of  claim 46  wherein A 5    is selected from the group consisting of substituted phenyl, heteroaromatic, and heterocyclic structures; K is a linear alkylene chain of  1  to  4  methylene units in length; R   16    is selected from the group consisting of hydrogen, phenyl, substituted phenyl, heteroaromatic, arylcarbonyl, and arylcarbonylamino; R   17    is selected from the group consisting of hydrogen and methyl; or wherein R   16    and R   17    together represent a double bond attached to a diaryl substituted carbon; or R   16    and R   17    taken together represent attachment points for a spirocyclic ring moiety, preferably selected from the group consisting of  1 , 3   - dioxalane and  5 , 5   ′- oxazolidin -   3   - one; and R   18    is selected from the group consisting of hydrogen and arylcarbonylamino.    
     
     
       48. The method of  claim 46  wherein the compound is selected from the group consisting, of piperoxan, proroxan, fenspiride, indoramin, and lidanserin.  
     
     
       49. The method of  claim 13  wherein the compound has the structure of Formula X: 
                   
       
         wherein A 
         6  
         is selected from the group consisting of aryl, aryloxy, heteroaryl, heteroaryloxy, arylthio, heteroarylthio, arylalkyl, and heteroarylalkyl, which are optionally substituted by one or more radicals selected from the group consisting of chloro, hydroxyl, alkoxy, alkyl, amino, aminoalkyl, arylsulfonamino, alkylsulfonamino, aminocarbonyl, aminosulfonyl, thiol, aryl, heteroaryl, and alkylthio; R 
         19 
         , R 
         22 
         , and R 
         23  
         are independently selected from the group consisting of hydrogen and alkyl; R 
         20  
         is selected from the group consisting of hydrogen and alkyl; and R 
         21  
         is defined as:  
         
           
           
               
               
           
         
       
       
         wherein R 
         24  
         and R 
         25  
         are independently selected from the group consisting of hydrogen and alkyl; A 
         7  
         is phenyl or substituted phenyl; and n″″ represents a value of  0  to  4  methylene units; or R 
         20  
         and R 
         21  
         taken together represent contact points which form a pyrrolidine or piperidine, which may be further substituted; or a pharmaceutically acceptable salt thereof.  
       
     
     
       50. The method of  claim 49  wherein A 6    is selected from the group consisting of phenyl, substituted phenyl, carbostyril,  2 , 3   - dihydrobenzo[b]thiophen -   5   - yl, and thiazolyl -   2   - thio; R   19    is hydrogen; R   23    is hydrogen or methyl; R   20    is hydrogen; R   24    and R   25    are independently hydrogen or methyl; and A   7    is phenyl.    
     
     
       51. The method of  claim 49  wherein R 20    and R   21    together form a piperidine moiety, which is further substituted by a phenylmethyl substituent.    
     
     
       52. The method of  claim 49  wherein the compound is selected from the group consisting of labetalol, amosulalol, arotinolol, brefanolol, ifenprodil and tibalosin.  
     
     
       53. The method of  claim 13  wherein the compound has the structure of Formula XI: 
                   
       
         wherein R 
         26  
         and R 
         27  
         are independently selected from the group consisting of alkyl, arylalkyl, aryloxyalkyl, and heteroalkyl; or R 
         26  
         and R 
         27  
         taken together represent a ring structure; and G represents a suitable leaving group substituent selected from the group consisting of halogen, alkylsulfonyloxy, and arylsulfonyloxy; or a pharmaceutically acceptable salt thereof.  
       
     
     
       54. The method of  claim 53  wherein R 26    and R   27    are independently selected from the group consisting of phenylalkyl and phenyloxyalkyl, and G is chloro.    
     
     
       55. The method of  claim 53  wherein the compound is selected from the group consisting of phenoxybenzamine and dibenzamine.  
     
     
       56. The method of  claim 13  wherein the compound has the structure of Formula XII: 
                   
       
         wherein A 
         8  
         is selected from the group consisting of aryl and heteroaryl, which may be substituted by one or more radicals independently selected from the group consisting of alkyl, halogen, alkoxy, alkylthio, hydroxyl, amino, arylsulfonylamino, and carboxamido; and R 
         28  
         is selected from the group consisting of hydrogen and alkyl; or a pharmaceutically acceptable salt thereof.  
       
     
     
       57. The method of  claim 56  wherein A 8    is phenyl or substituted phenyl, and R   28    is hydrogen or methyl.    
     
     
       58. The method of  claim 56  wherein the compound is selected from the group consisting of detomidine and medetomidine.  
     
     
       59. The method of  claim 13  wherein the compound is selected from the structural class of compounds known generically as the Rauwolfia alkaloids.  
     
     
       60. The method of  claim 59  wherein the compound is selected from the group consisting of reserpine, mediodespidine, deserpidine, rauwulscine, and extracts of Rauwolfia serpentina; or a pharmaceutically acceptable salt thereof.  
     
     
       61. The method of  claim 13  wherein the compound is selected from the class of compounds known generally as the ergot alkaloids.  
     
     
       62. The method of  claim 60  wherein the compound is selected from the group consisting of nicergoline, dihydroergocornine, dihydroergocryptine, dihydroergocristine, amsulosin, BAM-   1125 , and a mixture of hydrogenated derivatives of the ergotoxine alkaloids.    
     
     
       63. The method of  claim 13  wherein the compound has the structure of Formula XIII: 
                   
       
         wherein each of R 
         32  
         through R 
         35  
         is independently selected from the group consisting of hydrido, alkyl, haloalkyl, mercapto, alkylthio, cyano, alkoxy, alkoxyalkyl and cycloalkyl; J is selected from oxygen and sulfur; R 
         29  
         and R 
         30  
         are independently selected from the group consisting of hydrido and alkyl; R 
         31  
         is selected from the group consisting of hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, arylalkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, and alkylsulfinyl.  
       
     
     
       64. The method of  claim 13  wherein the compound has the structure of Formula XIV: 
                   
       
         wherein each of R 
         36 
         , R 
         37  
         and R 
         40  
         through R 
         43  
         is independently selected from the group consisting of hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, aryl, alkoxy, arylalkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl and alkynyl; or R 
         36  
         and R 
         37  
         together form oxo or thio; r is a number selected from zero through six, inclusive; and R 
         38  
         and R 
         39  
         are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl.  
       
     
     
       65. The method of  claim 64  wherein R 36   , R   37    and R   40    through R   43    are independently selected from the group consisting of hydrido, hydroxy, alkyl, phenalkyl, phenyl, alkoxy, benzyloxy, phenoxy, alkoxyalkyl, hydroxyalkyl, halo, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl; r is a number selected from zero through four, inclusive; and R   38    and R   39    are independently selected from the group consisting of hydrido, alkyl, amino, monoalkylamino, dialkylamino, phenyl and phenalkyl.    
     
     
       66. The method of  claim 64  where in each of R 36   , R   37    and R   40    are independently selected from the group consisting of hydrido, hydroxy, alkyl, alkoxy, amino, monoalkylamino, carboxy, carboxyalkyl and alkanoyl; r is a number selected from zero through three, inclusive; R   38    and R   39    are selected from the group consisting of hydrido, alkyl, amino and monoalkylamino; and R   41    through R   43    are selected from the group consisting of hydrido and alkyl.    
     
     
       67. The method of  claim 64  wherein the compound is  5 - n - butylpicolinic acid hydrazide  ( fusaric acid hydrazide ).  
     
     
       68. The method of  claim 13  wherein the compound has the structure of Formula XV: 
                   
       
         wherein R 
         44  
         through R 
         48  
         are independently selected from the group consisting of hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, aryloxy, alkoxy, alkylthio, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, amido, alkylamido, hydroxyamino, carboxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alkynyl, cyanoamino, tetrazolyl, thiocarbamoyl, aminomethyl, alkylsulfanamido, nitro, alkylsulfonyloxy, formoyl and alkoxycarbonyl; with the proviso that at least one of R 
         44  
         through R 
         48  
         is  
         
           
           
               
               
           
         
       
         wherein A′ is —CO—R   49    or —NR   51   R   52    wherein R   49    is selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylthio, phenyl, phenoxy, benzyl, benzyloxy, —OR   50    and —NR   53   R   54   , wherein R   50    is selected from the group consisting of hydrido, alkyl, cycloalkyl, cycloalkylalkyl, phenyl and benzyl; R   51    through R   54    are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; and t is a number selected from zero through four, inclusive; or a pharmaceutically - acceptable salt thereof.    
     
     
       69. The method of  claim 13  wherein the compound has the structure of Formula XVI: 
                   
       
         wherein R 
         49  
         through R 
         52  
         are independently selected from the group consisting of hydrido, hydroxy, alkyl, cycloalkyl, phenyl, benzyl, alkoxy, phenoxy, benzyloxy, alkoxyalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, amido, alkylamido, hydroxyamino, carboxyl, carboxyalkyl, alkanoyl, cyanoamino, thiocarbamoyl, aminomethyl, nitro, formoyl, formyl and alkoxycarbonyl; and R 
         53  
         is selected from the group consisting of hydrido, alkyl, phenyl and benzyl.  
       
     
     
       70. The method of  claim 68  wherein the compound is selected from the group consisting of  5 - n - butylpicolinic acid  ( fusaric acid ) ; picolinic acid;  5   - nitropicolinic acid;  5   - aminopicolinic acid;  5   - N - acetylaminopicolinic acid;  5   - N - propionylaminopicolinic acid;  5   - N - hydroxyaminopicolinic acid;  5   - iodopicolinic acid;  5   - bromopicolinic acid;  5   - chloropicolinic acid;  5   - hydroxypicolinic acid;  5   - methoxypicolinic acid;  5   - N - propoxypicolinic acid;  5   - N - butoxypicolinic acid;  5   - cyanopicolinic acid;  5   - carboxyl - picolinic acid;  5   - n - butyl -   4   - nitropicolinic acid;  5   - n - butyl -   4   - methoxypicolinic acid;  5   - n - butyl -   4   - ethoxypicolinic acid;  5   - n - butyl -   4   - aminopicolinic acid;  5   - n - butyl -   4   - hydroxyaminopicolinic acid; and  5   - n - butyl -   4   - methylpicolinic acid.    
     
     
       71. The method of  claim 13  wherein the compound has the structure of Formula XVII: 
                   
         wherein R   55    is selected from the group consisting of hydrido, hydroxy, alkyl, amino and alkoxy; R   56    is selected from the group consisting of hydrido, hydroxy and alkyl; R   57    and R   58    are independently selected from the group consisting of hydrido, alkyl and phenalkyl; R   59    is selected from the group consisting of hydrido and R   60    C— with R   60    selected from the group consisting of alkyl, phenyl and phenalkyl; u is a number from one to three, inclusive; and v is a number from zero to two, inclusive; or a pharmaceutically - acceptable salt thereof.    
     
     
       72. The method of  claim 71  wherein R 55  is selected from the group consisting of hydroxy and lower alkoxy; R 56    is hydrido; R   57    is selected from the group consisting of hydrido and lower alkyl; R   58    is hydrido; R   59    is selected from the group consisting of hydrido and R   60    C— with R   60    selected from the group consisting of lower alkyl and phenyl; u is two; and v is a number from zero to two, inclusive.    
     
     
       73. The method of  claim 13  wherein the compound has the structure of Formula XVIII: 
                   
         wherein R   61    is selected from the group consisting of hydroxy and lower alkyl; R   57    is selected from the group consisting of hydrido and lower alkyl; R   59    is selected from the group consisting of hydrido and R   60   C, where R   60    is selected from the group consisting of lower alkyl and phenyl, v is a number from zero to two, inclusive, R   61    is hydroxy or lower alkyl, and wherein the compound is selected from the group consisting of  1   -(   3   - mercapto -   2   - methyl -   1   - oxopropyl )- L - proline and  1   -(   2   - mercaptacetyl )- L - proline.    
     
     
       74. The method of  claim 13  wherein the compound is selected from the group consisting of bretylium and methylapogalanthamine.  
     
     
       75. The method of  claim 13  wherein the compound is applied in an ointment or lotion.  
     
     
       76. The method of  claim 13  wherein the compound is applied in a transdermal patch.  
     
     
       77. The method of  claim 66 , wherein R 36    and R   37    are hydrido; r is selected from the group consisting of zero, one, and two; R   38    is selected from the group consisting of hydrido, alkyl, and amino; and R   39    is selected from the group consisting of hydrido and alkyl.