In vivo screening method of therapeutic agent for memory/learning dysfunctions by schizophrenia

Abstract

A method of evaluating memory/learning functions with the use of a model with glutamic acid N-methyl-D-aspartate (NMDA) type receptor hypofunction as an animal model for schizophrenia and with the use of reference memory task, wherein there has been found concrete means for detecting any differences in activity between typical anti-psychosis drugs and atypical anti-psychosis drugs is found. An in vivo animal model for screening of a therapeutic agent for improving cognitive dysfunction by schizophrenia is provided.

1 . An in vivo screening method for predicting whether or not a test compound is capable of improving the memory/learning dysfunctions by schizophrenia, wherein said method comprises a step of evaluating the memory/learning functions by employing a model showing glutamic acid N-methyl-D-aspartate (NMDA) type receptor hypofunction as an animal model for schizophrenia, and a reference memory task.  
   
   
       2 . The method according to  claim 1 , wherein the reference memory task is a passive avoidance task, an active avoidance task, a water maze task, a radial maze task, a T or Y maze task, a place recognition task, an object recognition task, an autoshaping learning task, or a lever-pressing task.  
   
   
       3 . The method according to  claim 1 , wherein the reference memory task is composed of two sessions of training and testing, and in the training session the animals are made to learn either of the tasks described in  claim 2  and to acquire the memory of said task, and in the testing session being carried out after a prescribed period from the training session, the retention and retrieval ability of said memory of the animals are quantified.  
   
   
       4 . The method according to  claim 1 , wherein the model showing an NMDA type receptor hypofunction is produced by administering a compound having an NMDA type receptor antagonistic activity, e.g., MK-801, phencyclidine (PCP), ketamine, or a derivative thereof, to the animals in both of the training session and the testing session of the reference memory task, or by chronically administering said compound or a derivative thereof to the animals during the period including the training session and the testing session.  
   
   
       5 . The method according to  claim 1 , wherein the model showing an NMDA type receptor hypofunction is an animal model associated with an NMDA type receptor hypofunction due to variation, overexpression, or deficiency of gene of constitutive proteins or relevant proteins of an NMDA type receptor in both of the training session and the testing session of the reference memory task.  
   
   
       6 . A therapeutic agent for the memory/learning dysfunctions by schizophrenia, which comprises a substance selected by a screening method as set forth in any one of  claims 1  to  5  as an active ingredient.  
   
   
       7 . A therapeutic agent for the memory/learning dysfunctions by schizophrenia, which comprises a serotonin 5-HT 1A antagonist selected by a screening method as set forth in any one of  claims 1  to  5  as an active ingredient.  
   
   
       8 . A therapeutic agent for the memory/learning dysfunctions by schizophrenia, which comprises a choline acetylase inhibitor selected by a screening method as set forth in any one of  claims 1  to  5  as an active ingredient.  
   
   
       9 . A therapeutic agent for the memory/learning dysfunctions by schizophrenia, which comprises aricept as an active ingredient.  
   
   
       10 . A therapeutic agent for the memory/learning dysfunctions by schizophrenia, which comprises quetiapine as an active ingredient.  
   
   
       11 . The therapeutic agent for the memory/learning dysfunctions by schizophrenia according to  claim 10 , which comprises as an active ingredient quetiapine in a daily dose of 5 to 270 mg.  
   
   
       12 . The therapeutic agent for the memory/learning dysfunctions by schizophrenia according to  claim 10 , which comprises as an active ingredient quetiapine in a daily dose of 15 to 90 mg.  
   
   
       13 . A therapeutic agent for the memory/learning dysfunctions by schizophrenia, which comprises clozapine as an active ingredient.  
   
   
       14 . The therapeutic agent for the memory/learning dysfunctions by schizophrenia according to  claim 13 , which comprises as an active ingredient clozapine in a daily dose of 0.2 to 34.5 mg.  
   
   
       15 . The therapeutic agent for the memory/learning dysfunctions by schizophrenia according to  claim 13 , which comprises as an active ingredient clozapine in a daily dose of 0.7 to 11.5 mg.  
   
   
       16 . A therapeutic agent for the memory/learning dysfunctions by schizophrenia, which comprises as an active ingredient an imide derivative of the formula [1]:  
     
       
         
         
             
             
         
       
     
     {wherein Z is a group of the formula:  
     
       
         
         
             
             
         
       
     
     (in which B is a carbonyl or a sulfonyl; R 1  R 2 , R 3  and R 4  are independently a hydrogen atom or a lower alkyl, provided that R 1  and R 2 , or R 1  and R 3  may combine each other to form a hydrocarbon ring, or R 1  and R 3  may combine each other to form an aromatic hydrocarbon ring; said hydrocarbon ring may optionally be cross-linked with a lower alkylene or an oxygen atom; said lower alkylene and hydrocarbon ring may optionally be substituted by at least one alkyl; and n is 0 or 1), 
 D is a group of the formula:  
   —(CH 2 ) p -A-(CH 2 ) q — 
 (in which A is a hydrocarbon ring optionally be cross-linked with a lower alkylene or an oxygen atom; said lower alkylene and said hydrocarbon ring may optionally be substituted by at least one alkyl; and p and q are independently 0, 1 or 2),  
 G is N, CH or COH, and —Ar is an aromatic heterocyclic group, an aromatic hydrocarbon group, benzoyl, phenoxy, or phenylthio, or G is a carbon atom, and —Ar is a biphenylmethylidene,  
 where said aromatic heterocyclic group, aromatic hydrocarbon group, benzoyl, phenoxy, phenylthio, and biphenylmethylidene may optionally be substituted by at least one group selected from a lower alkyl, a lower alkoxy and a halogen atom},  
 or an acid addition salt thereof.  
 
   
   
       17 . The therapeutic agent for the memory/learning dysfunctions by schizophrenia comprising as an active ingredient the imide derivative or an acid addition salt thereof according to  claim 16 , wherein Ar is an aromatic heterobicyclic group, naphthyl, benzoyl, phenoxy or phenylthio, and G is N, CH or COH, or —Ar is a biphenylmethylidene, and G is a carbon atom (said aromatic heterobicyclic group, naphthyl, benzoyl, phenoxy, phenylthio and biphenylmethylidene may optionally be substituted by at least one group selected from a lower alkyl, a lower alkoxy and a halogen atom).  
   
   
       18 . The therapeutic agent for the memory/learning dysfunctions by schizophrenia comprising as an active ingredient the imide derivative or an acid addition salt thereof according to  claim 16 , wherein Ar is an aromatic heterocyclic group condensed with a benzene ring, or naphthyl, benzoyl, phenoxy or phenylthio (said aromatic heterocyclic group condensed with a benzene ring, naphthyl, benzoyl, phenoxy, and phenylthio may optionally be substituted by at least one group selected from a lower alkyl, a lower alkoxy and a halogen atom), and G is N, CH or COH.  
   
   
       19 . The therapeutic agent for the memory/learning dysfunctions by schizophrenia comprising as an active ingredient the imide derivative or an acid addition salt thereof according to  claim 16 , wherein Z is a group of the formula:  
     
       
         
         
             
             
         
       
     
     (in which -L- is a single bond or a double bond, E is a lower alkylene optionally substituted by a lower alkyl, or an oxygen atom, R 5  is a hydrogen atom or a lower alkyl, and B is the same as defined in claim  14 ); 
 a group of the formula:  
                     
 (in which -L-, E, R 5  and B are as defined above);  
 a group of the formula:  
                     
 (in which R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15  are independently a hydrogen atom or a lower alkyl, or the adjacent two groups of R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15  may combine each other to form a double bond, and B is as defined above);  
 a group of the formula:  
                     
 (in which R 16  and R 17  are independently a hydrogen atom or a lower alkyl, or R 16  and R 17  may combine each other to form a saturated hydrocarbon ring, and R 5  and B are as defined above); or  
 a group of the formula:  
                     
 (in which B is as defined above).  
 
   
   
       20 . A therapeutic agent for the memory/learning dysfunctions by schizophrenia comprising as an active ingredient the imide derivative or an acid addition salt thereof, wherein the compound of the formula [1] is lurasidone:  
     
       
         
         
             
             
         
       
     
   
   
       21 . A therapeutic agent for the memory/learning dysfunctions by schizophrenia, which comprises as an active ingredient a compound of the formula (2):  
     
       
         
         
             
             
         
       
     
     wherein Z is a divalent sulfur, imino, or lower alkylimino; 
 R 11  is a hydrogen atom or an alkyl having 1 to 5 carbon atoms;  
 R 12  is a hydrogen atom, an alkyl having 1 to 5 carbon atoms, a phenyl, an R 15 -substituted phenyl, an aminoalkyl having 1 to 5 carbon atoms, a lower alkylaminoalkyl having 2 to 8 carbon atoms, a lower alkylamino, an amino, or a lower alkylamino; or  
 R 11  and R 12  may combine each other together with N to form a 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl, a 4-lower alkyl-1-piperazinyl, a 4-(hydroxy-lower alkyl)-1-piperazinyl or a 4-(lower alkoxy-lower alkyl)-1-piperazinyl; and  
 R 13 , R 14 , and R 15  are independently a hydrogen atom, a halogen atom, a hydroxy group, a trifluoromethyl, a lower alkyl, a lower alkoxy, or a lower alkylthio,  
 or an acid addition salt thereof.