Treatment of parkinson's disease and enhancement of dopamine signal using pde 10 inhibitor

Abstract

The present invention relates to a therapeutic or prophylactic method for treating Parkinson's disease by administering an effective amount of a compound having a phosphodiesterase 10 inhibitory activity; and also relates to a pharmaceutical composition for treatment or prophylaxis of Parkinson's disease comprising as an active ingredient a compound having a phosphodiesterase 10 inhibitory activity. Moreover, the present invention relates to a method for enhancing dopamine signal in the brain, which comprises administering an effective amount of a compound having a phosphodiesterase 10 inhibitory activity; and also relates to pharmaceutical composition for enhancing dopamine signal in brain comprising as an active ingredient a compound having a phosphodiesterase 10 inhibitory activity.

1 . A method for enhancing dopamine signals in the brain, which comprises administering to a patient of Parkinson's disease an effective amount of a compound having a phosphodiesterase 10 inhibitory activity together with inducing dopamine signals by L-dopa administration or by administration of a dopamine receptor agonist, and thereby enhancing dopamine signals in the brain of said patient of Parkinson's disease; wherein the compound having phosphodiesterase 10 inhibitory activity is not: a non-specific PDE inhibitor selected from caffeine, IBMX, theophyllamine, dipyridamole, papaverine, and theophylline; a PDE5 inhibitor sildenafil; or a PDE4 inhibitor rolipram. 
     
     
         2 . The method according to  claim 1 , wherein the compound having a phosphodiesterase 10 inhibitory activity has the following characteristics:
 1) IC 50  value is 300 nM or less as measured under condition of a substrate cAMP concentration of 0.25 μM, or   2) Ki value for phosphodiesterase 10 is 150 nM or less.   
     
     
         3 . The method according to  claim 1 , wherein the compound having a phosphodiesterase 10 inhibitory activity is characterized by its inhibitory activity or affinity for phosphodiesterase 10 being 100 times or more as high, as compared to its inhibitory activity or affinity for phosphodiesterases 1, 3, 4, 5 and 6. 
     
     
         4 . The method according to  claim 1  or  3 , wherein the dopamine signals are enhanced in a part of the brain, selected from the group consisting of corpus striatum, nucleus accumbens, olfactory tubercle and frontal lobe. 
     
     
         5 . The method according to  claim 1  or  3 , wherein the dopamine signals are enhanced in the corpus striatum. 
     
     
         6 . The method according to  claim 1  or  3 , wherein the dopamine signals are those induced by L-dopa administration. 
     
     
         7 . The method according to  claim 1  or  3 , wherein the dopamine signals are those induced by administration of a dopamine receptor agonist. 
     
     
         8 . The method according to  claim 1  or  3 , wherein the dopamine signals are those induced by administration of a dopamine type 1 receptor agonist. 
     
     
         9 . The method according to  claim 1  or  3 , wherein the dopamine signals are those induced by administration of a dopamine type 2 receptor agonist. 
     
     
         10 . The method according to  claim 1  or  3 , wherein the dopamine signals are those induced by administration of a dopamine type 2 receptor selective agonist. 
     
     
         11 . The method according to  claim 1  or  3 , wherein the dopamine signals are those induced by administration of bromocriptine. 
     
     
         12 . The method according to  claim 1  or  3 , wherein the compound having a phosphodiesterase 10 inhibitory activity has the following characteristics:
 1) IC 50  value is 10 nM or less as measured under condition of a substrate cAMP concentration of 0.25 μM, or 
 2) Ki value for phosphodiesterase 10 is 5 nM or less.