Patent Publication Number: US-11377421-B2

Title: Psychotropic agents and uses thereof

Description:
PRIORITY CLAIM 
     This application claims the benefit of U.S. Provisional Application No. 62/734,974, filed Sep. 21, 2018 and is a continuation in part of PCT/US2018/33552 filed May 18, 2018, which claims the benefit of 62/508,263 filed May 18, 2017, This application is a continuation in part of Ser. No. 16/383,933, filed Apr. 15, 2019, which is a continuation of Ser. No. 15/824,966, filed Nov. 28, 2017, now U.S. Pat. No. 10,259,786 issued Apr. 16, 2019, which claims the benefit of 62/508,263 filed May 18, 2017, all of which are incorporated herein by reference in their entireties. 
    
    
     FIELD OF THE INVENTION 
     The present invention is generally in the field of pharmaceutical compositions and methods for the treatment of neuropsychiatric and/or psychological diseases or disorders. 
     BACKGROUND 
     Schizophrenia is a chronic debilitating mental illness affecting about one percent of the population. The disease manifests in delusional behavior, dysfunctional thinking, agitated body movement, social withdrawal, and depression. Schizophrenia patients suffer a profoundly reduced quality of life, and are ten times more likely to commit suicide that the general population. 
     Dopamine (particularly D 2  and D 3 ) antagonists are well recognized as improving symptoms of schizophrenia, and have been used clinically as such for decades. In the past twenty years it has become recognized that treatment of schizophrenia, as with many mental illnesses, benefits from engaging multiple receptors including serotonergic and adrenergic. Despite, literally, dozens of approved drugs to treat schizophrenia the disease remains poorly treated in many patients. Side effects of current medications include: dyskinesia, akathisia, weight gain, mood disturbances, sexual dysfunction, sedation, orthostatic hypotension, hypersalivation, and (in some cases) arganulocytosis. 
     Amisulpride (4-amino-N-(((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide) is an antipsychotic patented in 1981. Amisulpride binds selectively to the human dopaminergic D 2  (K i  2.8 nM) and D 3  (K i  3.2 nM) receptor subtypes without any affinity for D 1 , D 4  and D 5  receptor subtypes. Unlike classical and atypical neuroleptics, amisulpride displays low affinity for serotonin, alpha-adrenergic, histamine receptor subtypes, muscarinic receptors and sigma sites though it has also been demonstrated to bind 5-HT 2B  and HT 7a  receptors with low double digit nM K i . This ability of amisulpride to bind 5-HT receptors is thought to result in amisulpride&#39;s ability to treat symptoms of depression (sometimes noted in schizophrenia patients). Interestingly, compared to other antipsychotics, amisulpride is not noted to have any activity at the 5-HT 2a  receptor. 
     Despite the unique activities of amisulpride, amisulpride has low ability to cross blood brain barrier (BBB) to interact with the receptors in the brain. In a 2014 study, passive diffusion of amisulpride across a PAMPA membrane (P e ) was the lowest of 30 psychiatric drugs tested. Thus, dosing of amisulpride is high, typically 400 to 800 mg/d (though up to 1,200 mg/day is not uncommon). Such a high dose may cause adverse effects to the treated subjects. 
     SUMMARY OF THE INVENTION 
     Provided herein are amisulpride derivatives and pharmaceutical compositions thereof. In certain embodiments, the amisulpride derivatives disclosed herein are dopamine and/or serotonin antagonists. In certain embodiments, the amisulpride derivatives disclosed herein have improved membrane (e.g., BBB) permeability compared to amisulpride. In certain embodiments, the amisulpride derivatives can act as central nervous system (CNS) dopamine and/or serotonin antagonists. These amisulpride derivatives have structures of Formula I, Formula IA, Formula IB or Formula IC disclosed herein, including pharmaceutically acceptable salts thereof, and stereoisomers thereof (e.g., Formula I-S, Formula I-R, Formula IA-S, Formula IA-R, Formula IB-S, Formula IB-R, Formula IC-S, and Formula IC-R). Provided herein are also deuterated analogs of amisulpride and deuterated analogs of the amisulpride derivatives disclosed herein. 
     Also provided herein are methods for delivering a serotonin (e.g., 5-HT 2a , 5-HT 7 ) receptor antagonist to the brain of a subject comprising administering to the subject an amisulpride derivative disclosed herein or a pharmaceutical composition thereof; and the serotonin receptor antagonist level in the brain is higher than administering to the subject amisulpride (racemic mixture) at a comparable dose. 
     Also provided herein are methods for antagonizing a serotonin (e.g., 5-HT 2a , 5-HT 7 ) receptor in a subject comprising administering to the subject one or more R enantiomers selected from the group consisting of the R enantiomer of amisulpride, the R enantiomer of an amisulpride derivative disclosed herein (e.g., the R enantiomer of 4-amino substituted derivatives amisulpride), the R enantiomer of a deuterated analog of amisulpride, and the R enantiomer of a deuterated analog of an amisulpride derivative disclosed herein, or a pharmaceutical composition comprising the one or more R enantiomers, either individually or in combination with one or more of other CNS active agents. In certain embodiments, the one or more R enantiomers are substantially enantiomerically pure. 
     Also provided herein are methods for modulating a 5-HT 7  receptor in a subject comprises administering to the subject a therapeutically effective amount of one or more R enantiomers selected from the group consisting of the R enantiomer of amisulpride, the R enantiomer of an amisulpride derivative disclosed herein (e.g., the R enantiomer of 4-amino substituted derivatives amisulpride), the R enantiomer of a deuterated analog of amisulpride, and the R enantiomer of a deuterated analog of an amisulpride derivative disclosed herein, or a pharmaceutical composition comprising the one or more R enantiomers, either individually or in combination with one or more other CNS active agents. In certain embodiments, the one or more R enantiomers are substantially enantiomerically pure. 
     Provided herein are methods for modulating both D 2/3  and 5-HT 7  receptors in a subject comprising administering to the subject a therapeutically effective amount of one or more R enantiomers selected from the group consisting of the R enantiomer of amisulpride, the R enantiomer of an amisulpride derivative disclosed herein (e.g., the R enantiomer of 4-amino substituted derivatives amisulpride), the R enantiomer of a deuterated analog of amisulpride, and the R enantiomer of a deuterated analog of an amisulpride derivative disclosed herein, or a pharmaceutical composition comprising the one or more R enantiomers, either individually or in combination with one or more other CNS active agents. In certain embodiments, the one or more R enantiomers are substantially enantiomerically pure. 
     Also provided herein are methods for treating one or more conditions responsive to modulation of dopamine and/or serotonin (e.g., 5-HT 2a , 5-HT 7 ) and/or α2 receptor in a subject comprising administering to the subject a therapeutically effective amount of one or more R enantiomers selected from the group consisting of the R enantiomer of amisulpride, the R enantiomer of an amisulpride derivative disclosed herein (e.g., the R enantiomer of 4-amino substituted derivatives amisulpride), the R enantiomer of a deuterated analog of amisulpride, and the R enantiomer of a deuterated analog of an amisulpride derivative disclosed herein, or a pharmaceutical composition comprising the one or more R enantiomers, either individually or in combination with one or more other CNS active agents. In certain embodiments, the one or more R enantiomers are substantially enantiomerically pure. In certain embodiments, the one or more conditions are responsive to modulation of 5-HT 7  receptor (e.g., without limitation, anxiety, depression, migraines, and obsessive-compulsive disorder). 15-21    
     Provided herein are methods for treating one or more disorders associated with an abnormality in levels of dopamine and/or serotonin in the brain in a subject comprising administering to the subject a therapeutically effective amount of one or more R enantiomers selected from the group consisting of the R enantiomer of amisulpride, the R enantiomer of an amisulpride derivative disclosed herein (e.g., the R enantiomer of 4-amino substituted derivatives amisulpride), the R enantiomer of a deuterated analog of amisulpride, and the R enantiomer of a deuterated analog of an amisulpride derivative disclosed herein, or a pharmaceutical composition comprising the one or more R enantiomers, either individually or in combination with one or more other CNS active agents. In certain embodiments, the one or more R enantiomers and/or the pharmaceutical composition comprising the one or more R enantiomers are substantially enantiomerically pure. In certain embodiments, the one or more disorders are selected from the group consisting of anxiety, depression, migraines, and obsessive-compulsive disorder. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1A : Novel object exploration data from a sub-chronic PCP NOR study in rats (±SEM, n=10/group). Differences in Discrimination index ((time spent exploring novel—time spent exploring familiar)/total exploration time) are depicted. 
         FIG. 1B : Discrimination index data from a sub-chronic PCR NOR study in rates (n=10/group). Differences in discrimination index ((time spent exploring novel—time spent exploring familiar)/total exploration time) are depicted. 
         FIG. 2 : Total Ambulatory Distance (over 1 hour)±SEM (n=10/group). p&lt;0.05 for all treated groups compared to amphetamine. 
         FIG. 3 : Binding of Compounds 102, 103, 104, and amisulpride (101) to 5-HT 7  receptor. 
         FIG. 4 : Binding of amisulpride (Ami(rac)), R enantiomer of amisulpride (Ami(r)), and S enantiomer of amisulpride (Ami(s)) to 5-HT 7  receptor. 
         FIG. 5A : Binding of amisulpride (LB-101) to D 2  receptor. 
         FIG. 5B : Binding of Compounds 102 (LB-102), 103 (LB-103), and 104 (LB-104) to D 2  receptor. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     As disclosed herein, 4-amino substituted derivatives of amisulpride (also referred to as 4-amino amisulpride derivatives and 4-amino substituted amisulpride derivatives) showed improved membrane (e.g., BBB) permeability and may be used to target relevant receptors in the brain at a lower dose with less side effects to the treated subjects compared to amisulpride. For example, a 4-amino substituted amisulpride derivative Compound 102 (also referred to as LB-102, N-methyl amisulpride, N-methylated analogue of amisulpride, and 4-methylamino substituted amisulpride derivative) was prepared (Examples 1 and 2) and showed unexpectedly high membrane permeability improvement compared to that of amisulpride (Example 4, 216.7 time improvement at pH 7.4, and 87.5 time improvement at pH 5). Stereoisomers of Compound 102 (the S enantiomer of Compound 102 (Compound 103) and the R enantiomer of Compound 102 (Compound 104)) were also prepared (Example 3), as were other 4-amino amisulpride derivatives Compounds 105 to 110. Furthermore, the 4-amino substituted amisulpride derivatives showed effective binding to dopamine D 2  receptors and various CNS receptors (Examples 5-7). Unexpectedly, the 4-amino substituted amisulpride derivatives showed α2 (e.g., α2A, a2B, and α2C) receptor antagonism (Table 4, Example 7), while amisulpride displayed low affinity for α2 receptor. The 4-amino substituted amisulpride derivatives showed 5-HT 2a  receptor antagonism (Table 4, Example 7), while amisulpride is not noted to have any activity at the 5-HT 2a  receptor. Furthermore, Compound 102 and Compound 103 were shown to restore known object exploration behavior in rats with impaired ability to discern between novel and familiar object in a Novel Object Recognition (NOR) assay (Example 8). The normalized amphetamine hyperactivities of Compounds 102 and 103 were statistically superior to or indistinguishable from that of amisulpride in an amphetamine-induced Locomotor Activity (LMA) assay (Example 9). Furthermore, the stereoisomers of Compound 102 (Compound 103 and Compound 104) showed unexpectedly different K in their binding to 5-HT 7  receptor, with the R enantiomer of Compound 102 (Compound 104) afforded a K of 16 nM compared to a K of &gt;1,000 nM for the S enantiomer of Compound 102 (Compound 103) (Example 10). Unexpected the R enantiomer of amisulpride showed an unexpected lower K i  compared to the S enantiomer of amisulpride ( FIG. 4 ). The stereoisomers of Compound 102 (Compound 103 and Compound 104) showed different K i  in their binding to D 2  receptor, with the R enantiomer of Compound 102 (Compound 104) afforded a K of 14.1±2.2 nM compared to a K i  of 0.4±0.04 nM for the S enantiomer of Compound 102 (Compound 103) (Example 11,  FIG. 5B ). Compound 102 (LB-102) bound D 2  receptor with a K i  of 0.82±0.02 nm (Example 11,  FIG. 5B ), and amisulpride (LB-101) bound D 2  receptor with a K i  of 1.1±0.12 nm (Example 11,  FIG. 5A ). 
     4-Amino Substituted Amisulpride derivatives 
     Provided herein are amisulpride derivatives having a structure of Formula I: 
     
       
         
         
             
             
         
       
         
         
           
             including pharmaceutically acceptable salts and stereoisomers thereof, wherein: 
             R 1  is 
           
         
       
    
                         
and
         X and Z are the same or different and independently selected from the group consisting of hydrogen, alkyl (either branched or unbranched, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, and s-butyl), alkenyl (either branched or unbranched, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, and s-butyl), alkynyl (either branched or unbranched, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, and s-butyl), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl), heterocyclyl, heterocyclylalkyl, aryl (e.g., phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl), arylalkyl (e.g., —CH 2 C 6 H 5 , and —C 2 H 5 C 6 H 5 ), heteroarylalkyl (e.g., —CH 2 C 6 H 4 N, and —C 2 H 5 C 6 H 4 N), and heteroaryl with one or two or three or more hetero ring atoms (such as pyridine, pyrrole, furan, thiophene, or pyrimidine), optionally the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl groups are further substituted with one or more substitution groups selected from the group consisting of halogens such as chlorine, bromine and fluorine, amines, hydroxy groups, carboxylic acids, nitro groups, carbonyl and other alkyl and aryl groups as defined herein; with the proviso that at least one of X and Z is not hydrogen, and when R 1  is       

                         
R 1  may be bonded at any of the positions labeled with “*” as shown below:
 
     
       
         
         
             
             
         
       
     
     In certain embodiments, the amisulpride derivative is a stereoisomer having a structure of Formula I-S: 
     
       
         
         
             
             
         
       
         
         
           
             including pharmaceutically acceptable salts thereof, wherein Z, X, and R 1  are defined the same as above with respect to Formula I. 
           
         
       
    
     In certain embodiments, the amisulpride derivative is a stereoisomer having a structure of Formula I-R: 
     
       
         
         
             
             
         
       
         
         
           
             including pharmaceutically acceptable salts thereof, wherein Z, X, and R 1  are defined the same as above with respect to Formula I. 
           
         
       
    
     In certain embodiments, the amisulpride derivative is a 4-amino substituted derivative of amisulpride having a structure of Formula IA: 
     
       
         
         
             
             
         
       
         
         
           
             including pharmaceutically acceptable salts and stereoisomers thereof, and X and Z are defined the same as above with respect to Formula I. 
           
         
       
    
     In certain embodiments, the 4-amino substituted derivative of amisulpride is a stereoisomer having a structure of Formula IA-S: 
     
       
         
         
             
             
         
       
         
         
           
             including pharmaceutically acceptable salts thereof, and X and Z are defined the same as above with respect to Formula I. 
           
         
       
    
     In certain embodiments, the 4-amino substituted derivative of amisulpride is a stereoisomer having a structure of Formula IA-R: 
     
       
         
         
             
             
         
       
         
         
           
             including pharmaceutically acceptable salts thereof, and X and Z are defined the same as above with respect to Formula I. 
           
         
       
    
     In certain embodiments, the amisulpride derivative is a 4-amino substituted derivative of amisulpride having a structure of Formula IB: 
     
       
         
         
             
             
         
       
         
         
           
             including pharmaceutically acceptable salts and stereoisomers thereof, and Z is defined the same as above with respect to Formula I with the proviso that Z is not H. 
           
         
       
    
     In certain embodiments, the 4-amino substituted derivative of amisulpride is a stereoisomer having a structure of Formula IB-S: 
     
       
         
         
             
             
         
       
         
         
           
             including pharmaceutically acceptable salts thereof, and Z is defined the same as above with respect to Formula I with the proviso that Z is not H. 
           
         
       
    
     In certain embodiments, the 4-amino substituted derivative of amisulpride is a stereoisomer having a structure of Formula IB-R: 
     
       
         
         
             
             
         
       
         
         
           
             including pharmaceutically acceptable salts thereof, and Z is defined the same as above with respect to Formula I with the proviso that Z is not H. 
           
         
       
    
     In certain embodiments, the amisulpride derivative has a structure of Formula IC: 
     
       
         
         
             
             
         
       
         
         
           
             including pharmaceutically acceptable salts and stereoisomers thereof, and Z is defined the same as above with respect to Formula I with the proviso that Z is not H. 
           
         
       
    
     In certain embodiments, the amisulpride derivative is a stereoisomer having a structure of Formula IC-S: 
     
       
         
         
             
             
         
       
         
         
           
             including pharmaceutically acceptable salts thereof, and Z is defined the same as above with respect to Formula I with the proviso that Z is not H. 
           
         
       
    
     In certain embodiments, the amisulpride derivative is a stereoisomer having a structure of Formula IC-R: 
     
       
         
         
             
             
         
       
         
         
           
             including pharmaceutically acceptable salts thereof, and Z is defined the same as above with respect to Formula I with the proviso that Z is not H. 
           
         
       
    
     In certain embodiments, the amisulpride derivatives disclosed herein have greater membrane (e.g., BBB) permeability than amisulpride. In certain embodiments, the amisulpride derivatives disclosed herein are dopamine and/or serotonin and/or α2 antagonists. For example, the amisulpride derivatives disclosed herein bind to dopamine D 2  and/or D 3  receptors. In certain embodiments, the amisulpride derivatives disclosed herein more selectively bind to dopamine D 2  and/or D 3  receptor over dopamine D 1 , D 4  and/or D 5  receptor. In certain embodiments, the amisulpride derivatives disclosed herein are capable of interacting dopamine and/or serotonin and/or α2 receptors in CNS. 
     In certain embodiments, the R enantiomer of amisulpride or an amisulpride derivative disclosed herein is a better 5-HT 7  antagonist than the corresponding S enantiomer. In certain embodiments, the S enantiomer of amisulpride or S enantiomer of an amisulpride derivative disclosed herein is a better D 2  antagonist than the corresponding R enantiomer. In certain embodiments, the ratio of K i  of the S enantiomer of amisulpride or an amisulpride derivative disclosed herein compared to the corresponding R enantiomer (K i (S:R)) for 5-HT 7  receptor (K i (S:R) 5-HT7 ) is higher than the ratio of K i  of the corresponding R enantiomer compared to the S enantiomer (K i (R:S)) for D 2  receptor (K i (R:S) D2 ). In certain embodiments, K i (R:S) D2  of amisulpride or an amisulpride derivative disclosed herein is about 10 to about 100, about 20 to about 80, about 30 to about 60, about 30 to about 50, about 30 to about 40, or about 36; and K i (S:R) 5-HT7  of the same is at least 50, at least 62.5, at least 100, at least 500, or at least 1,000. 
     For example, K i (R:S) D2  of Compound 102 was about 36, while K i (S:R) 5-HT7  of Compound 102 was more than 62.5. 
     Provided herein are also deuterated analogs of amisulpride, deuterated analogs of the amisulpride derivatives disclosed herein, wherein one or more hydrogens of amisulpride or the amisulpride derivatives are replaced by deuterium. In certain embodiments, the one or more deuteriums in the deuterated analog are present in at least 100 times the natural abundance level. 
     Provided herein are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and one or more therapeutic compounds selected from the group consisting of amisulpride, amisulpride derivatives disclosed herein, and deuterated analogs disclosed herein. In certain embodiments, the pharmaceutical compositions disclosed herein comprises a pharmaceutically acceptable carrier and one or more R enantiomers selected from the group consisting of the R enantiomer of amisulpride, the R enantiomer of an amisulpride derivative disclosed herein (e.g., the R enantiomer of 4-amino substituted derivatives amisulpride), the R enantiomer of a deuterated analog of amisulpride, and the R enantiomer of a deuterated analog of an amisulpride derivative disclosed herein. In certain embodiments, the one or more R enantiomers the pharmaceutical compositions comprise are substantially enantiomerically pure, and such pharmaceutical compositions are also referred to as substantially enantiomerically pure pharmaceutical compositions. In certain embodiments, the term “substantially enantiomerically pure” means enantiomerical purity of about 50% or higher, about 60% or higher, about 70% or higher, about 80% or higher, about 90% or higher, about 95% or higher, or about 98% or higher. 
     Also provided herein are methods for delivering a dopamine and/or serotonin (e.g., 5-HT 2a , 5-HT 7 ) and/or α2 receptor antagonist to the brain of a subject comprising administering to the subject one or more of the amisulpride derivatives and deuterated analogs thereof disclosed herein, or a pharmaceutical composition thereof; and the dopamine and/or serotonin (e.g., 5-HT 2a , 5-HT 7 ) and/or α2 receptor antagonist level in the brain is higher than administering to the subject amisulpride (racemic mixture) at a comparable dose. In certain embodiments, the amisulpride derivatives, and/or deuterated analogs are substantially enantiomerically pure, e.g., enantiomerically pure R isomers. In certain embodiments, the pharmaceutical composition is substantially enantiomerically pure and comprises one or more substantially enantiomerically pure R enantiomers selected from the group consisting of the R enantiomer of an amisulpride derivative disclosed herein (e.g., the R enantiomer of 4-amino substituted derivatives amisulpride), the R enantiomer of a deuterated analog of amisulpride, and the R enantiomer of a deuterated analog of an amisulpride derivative disclosed herein. 
     Also provided herein are methods for antagonizing dopamine and/or serotonin (e.g., 5-HT 2a , 5-HT 7 ) and/or α2 receptor in a subject comprising administering to the subject one or more R enantiomers selected from the group consisting of the R enantiomer of amisulpride, the R enantiomer of an amisulpride derivative disclosed herein (e.g., the R enantiomer of 4-amino substituted derivatives amisulpride), the R enantiomer of a deuterated analog of amisulpride, and the R enantiomer of a deuterated analog of an amisulpride derivative disclosed herein, or a pharmaceutical composition comprising the one or more R enantiomers, either individually or in combination with one or more other CNS active agents. In certain embodiments, the one or more R enantiomers are substantially enantiomerically pure. 
     Also provided herein are methods for modulating a 5-HT 7  receptor in a subject comprises administering to the subject a therapeutically effective amount of one or more R enantiomers selected from the group consisting of the R enantiomer of amisulpride, the R enantiomer of an amisulpride derivative disclosed herein (e.g., the R enantiomer of 4-amino substituted derivatives amisulpride), the R enantiomer of a deuterated analog of amisulpride, and the R enantiomer of a deuterated analog of an amisulpride derivative disclosed herein, or a pharmaceutical composition comprising the one or more R enantiomers, either individually or in combination with one or more other CNS active agents. In certain embodiments, the one or more R enantiomers are substantially enantiomerically pure. 
     Provided herein are methods for modulating both D 2/3  and 5-HT 7  receptors in a subject comprising administering to the subject a therapeutically effective amount of one or more R enantiomers selected from the group consisting of the R enantiomer of amisulpride, the R enantiomer of an amisulpride derivative disclosed herein (e.g., the R enantiomer of 4-amino substituted derivatives amisulpride), the R enantiomer of a deuterated analog of amisulpride, and the R enantiomer of a deuterated analog of an amisulpride derivative disclosed herein, or a pharmaceutical composition comprising the one or more R enantiomers, either individually or in combination with one or more other CNS active agents. In certain embodiments, the one or more R enantiomers are substantially enantiomerically pure. 
     Also provided herein are methods for treating one or more conditions responsive to modulation of dopamine and/or serotonin (e.g., 5-HT 2a , 5-HT 7 ) and/or α2 receptor in a subject comprising administering to the subject a therapeutically effective amount of one or more R enantiomers selected from the group consisting of the R enantiomer of amisulpride, the R enantiomer of an amisulpride derivative disclosed herein (e.g., the R enantiomer of 4-amino substituted derivatives amisulpride), the R enantiomer of a deuterated analog of amisulpride, and the R enantiomer of a deuterated analog of an amisulpride derivative disclosed herein, or a pharmaceutical composition comprising the one or more R enantiomers, either individually or in combination with one or more other CNS active agents. In certain embodiments, the one or more R enantiomers are substantially enantiomerically pure. In certain embodiments, the one or more conditions are responsive to modulation of 5-HT 7  receptor (e.g., without limitation, anxiety, depression, migraines, and obsessive-compulsive disorder). 
     Provided herein are methods for treating one or more disorders associated with an abnormality in levels of dopamine and/or serotonin in the brain in a subject comprising administering to the subject a therapeutically effective amount of one or more R enantiomers selected from the group consisting of the R enantiomer of amisulpride, the R enantiomer of an amisulpride derivative disclosed herein (e.g., the R enantiomer of 4-amino substituted derivatives amisulpride), the R enantiomer of a deuterated analog of amisulpride, and the R enantiomer of a deuterated analog of an amisulpride derivative disclosed herein, or a pharmaceutical composition comprising the one or more R enantiomers, either individually or in combination with one or more other CNS active agents. In certain embodiments, the one or more R enantiomers and/or the pharmaceutical composition comprising the one or more R enantiomers are substantially enantiomerically pure. In certain embodiments, the one or more disorders are selected from the group consisting of anxiety, depression, migraines, and obsessive-compulsive disorder. 
     In certain embodiments, the R enantiomer of amisulpride or an amisulpride derivative disclosed herein is a better 5-HT 7  antagonist than the corresponding S enantiomer. In certain embodiments, the S enantiomer of amisulpride or an amisulpride derivative disclosed herein is a better D 2  antagonist than the corresponding R enantiomer. In certain embodiments, the ratio of K i  of the S enantiomer of amisulpride or an amisulpride derivative disclosed herein compared to the corresponding R enantiomer (K i (S:R)) for 5-HT 7  receptor (K i (S:R) 5-HT7 ) is higher than the ratio of K i  of the corresponding R enantiomer compared to the S enantiomer (K i (R:S)) for D 2  receptor (K i (R:S) D2 ). In certain embodiments, K i (R:S) D2  of amisulpride or an amisulpride derivative disclosed herein is about 10 to about 100, about 20 to about 80, about 30 to about 60, about 30 to about 50, about 30 to about 40, or about 36; and K i (S:R) 5-HT7  of the same is at least 50, at least 62.5, at least 100, at least 500, or at least 1,000. 
     In certain embodiments of the methods disclosed herein, the amisulpride derivative disclosed herein is N-methylated analogue of amisulpride, i.e., Compound 102. In certain embodiments of the methods disclosed herein, the R enantiomer of the amisulpride derivative disclosed herein is the R enantiomer of N-methylated analogue of amisulpride, i.e., Compound 104. 
     In certain embodiments of the methods disclosed herein, the therapeutically effective amount of the R enantiomer of an amisulpride derivative disclosed herein (e.g., the R enantiomer of 4-amino substituted derivatives amisulpride) and the R enantiomer of a deuterated analog of an amisulpride derivative disclosed herein, or a pharmaceutical composition thereof is lower than that of amisulpride. Accordingly, the methods disclosed herein may result in fewer adverse events to the subject treated. In certain embodiments of the methods disclosed herein, at least one of the one or more R enantiomers has a significantly lower degree of dopamine binding than the corresponding S enantiomer (K i (R:S) D2&gt;1 ), while at least one of the one or more R enantiomers has a significantly higher degree of serotonin binding than the corresponding S enantiomer (K i (S:R) 5HT7 ), therefore the methods disclosed herein are less likely to cause side effects driven by dopamine receptors (e.g., without limitation, extrapyramidal side effects or prolactin elevation). In certain embodiments, K i (R:S) D2 &lt;K i (S:R) 5HT7 . 
     Examples of conditions responsive to modulation of dopamine and/or serotonin (e.g., 5-HT 2a , 5-HT 7 ) and/or α2 receptor and/or disorders associated with an abnormality in levels of dopamine and/or serotonin in the brain include, e.g., without limitation, mental illnesses. Examples of the mental illnesses include, without limitation, schizophrenia, symptoms of schizophrenia, schizoaffective disorder bipolar disorder, anxiety, depression, migraines, obsessive-compulsive disorder, Parkinson&#39;s psychosis, Alzheimer&#39;s psychosis, oppositional defiant disorder, aggression, suicidality, hostility, personality disorders, autism, chronic fatigue syndrome, predominantly negative symptoms of schizophrenia, Charles Bonnet Syndrome, and Tourette&#39;s disorder. 
     As used herein, the singular for “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a cell” includes a plurality of cells, including mixtures thereof. Similarly, use of “a compound” for treatment of preparation of medicaments as described herein contemplates using one or more compounds of the invention for such treatment or preparation unless the context clearly dictates otherwise. 
     As used herein, the term “comprising” is intended to mean that the compositions and methods include the recited elements, but not excluding others. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like. “Consisting of” shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the composition of this invention. Embodiments defined by each of the transitional terms are within the scope of this invention. 
     The term “alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation. Unless otherwise specified, the term “alkyl” refers to a group having one, two, three, four, five, six, seven, or eight carbon atoms (for example, one to six carbon atoms, or one to four carbon atoms), and which is attached to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, s-butyl, n-pentyl, and s-pentyl. 
     The term “alkenyl” refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched or branched chain. Unless otherwise specified, the term “alkenyl” refers to a group having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. 
     The term “alkynyl” refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond. Unless otherwise specified, the term “alkynyl” refers to a group having in the range of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (for instance, 2 to 10, 2 to 10 carbon atoms), e.g., ethynyl, propynyl, and butnyl. 
     The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ring system of 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 
     The term “cycloalkylalkyl” refers to a cycloalkyl group as defined above directly bonded to an alkyl group as defined above. 
     The term “aryl” refers to a mono- or multi-cyclic aromatic radical having in the range of 6 up to 20 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl. 
     The term “arylalkyl” refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., —CH 2 C 6 H 5 , and —C 2 H 5 C 6 H 5 . 
     The term “heterocyclyl” refers to a non-aromatic 3 to 15-member ring radical which, consists of carbon atoms and at least one heteroatom selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. The heterocyclic ring radical may be a mono-, bi-, tri- or tetracyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized. 
     The term “heterocyclylalkyl” refers to a heterocyclyl group as defined above directly bonded to an alkyl group as defined above. 
     The term “heteroaryl” refers to an optionally substituted 5-14 member aromatic ring having one or more hetero ring atoms selected from the group consisting of N, O, and S as ring atoms. The heteroaryl may be a mono-, bi- or tricyclic ring system. Examples of such heteroaryl ring radicals includes, but are not limited to, oxazolyl, thiazolyl imidazolyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl and isoquinolyl. 
     The term “heteroarylalkyl” refers to an heteroaryl group as defined above directly bonded to an alkyl group as defined above, e.g., —CH 2 C 6 H 4 N, and —C 2 H 5 C 6 H 4 N. 
     The term “subject” refers to a mammal, such as a domestic pet (for example, a dog or cat), or human. In certain embodiments, the subject is a human. 
     The phrase “effective amount” refers to the amount which, when administered to a subject or patient for treating a disease, is sufficient to effect such treatment for the disease. 
     “Treatment” or “treating” includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g., arresting further development of the pathology and/or symptomatology), (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology and/or symptomatology), and/or (3) effecting any measurable decrease in a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease. 
     The term “pharmaceutically acceptable carrier” refers to a carrier that does not cause an allergic reaction or other untoward effect in patients to whom it is administered and are compatible with the other ingredients in the formulation. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices. For example, solid carriers/diluents include, but are not limited to, a gum, a starch (e.g., corn starch, pregelatinized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g., microcrystalline cellulose), an acrylate (e.g., polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof. Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the therapeutic agent. 
     The term “salt” used herein is not limited as long as the salt is formed with a compound of the amisulpride derivatives and is pharmaceutically acceptable; preferred examples of salts include a hydrohalide salt (for instance, hydrochloride, hydrobromide, hydroiodide and the like), an inorganic acid salt (for instance, sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate and the like), an organic carboxylate salt (for instance, acetate salt, maleate salt, tartrate salt, fumarate salt, citrate salt and the like), an organic sulfonate salt (for instance, methanesulfonate salt, ethanesulfonate salt, benzenesulfonate salt, toluenesulfonate salt, camphorsulfonate salt and the like), an amino acid salt (for instance, aspartate salt, glutamate salt and the like), a quaternary ammonium salt, and the like. In addition, hydrochloride salt, sulfate salt, methanesulfonate salt, acetate salt and the like are preferred as “pharmacologically acceptable salt” of the amisulpride derivatives disclosed herein. 
     Isomers of amisulpride or the amisulpride derivatives disclosed herein (e.g., geometric isomers, optical isomers, rotamers, tautomers, and the like) can be purified using general separation means, including for example recrystallization, optical resolution such as diastereomeric salt method, enzyme fractionation method, various chromatographies (for instance, thin layer chromatography, column chromatography, glass chromatography and the like) into a single isomer. 
     Pharmaceutical Formulations and Routes of Administration 
     The one or more therapeutic compounds disclosed herein (e.g., R enantiomer of amisulpride, the amisulpride derivatives disclosed herein, and/or the deuterated analogs disclosed herein) may be administered by a variety of routes including orally and by injection (e.g. subcutaneously, intravenously, and intraperitoneally). The therapeutic compound disclosed herein may be formulated into a pharmaceutical composition for use in the disclosed methods. Such compositions are prepared in accordance with acceptable pharmaceutical procedures such as described in Remington&#39;s Pharmaceutical Sciences, 17th edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Eaton, Pa. (1985), which is incorporated herein by reference. 
     The one or more therapeutic compounds disclosed herein may be administered orally in the form of a solid or liquid dosage form. In both, one or more therapeutic compounds disclosed herein may be coated in a material to protect it from the action of acids and other natural conditions which may inactivate the compound. The one or more therapeutic compounds disclosed herein may be formulated as aqueous solutions, liquid dispersions, (ingestible) tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers. The oral dosage forms may include excipients known in the art, such as binders, disintegrating agents, flavorants, antioxidants, and preservatives. Liquid dosage forms may include diluents such as saline or an aqueous buffer. 
     The one or more therapeutic compounds disclosed herein may also be administered by injection. Formulations suitable for injection may include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The pharmaceutical composition may be sterile and be fluid to the extent that easy syringability exists. It may be stable under the conditions of manufacture and storage and be preserved against the contaminating action of microorganisms such as bacteria and fungi. The pharmaceutically acceptable carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, and ascorbic acid. In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin. 
     Sterile injectable solutions can be prepared by incorporating the one or more therapeutic compounds in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the one or more therapeutic compounds into a sterile carrier which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation include vacuum drying and freeze-drying which yields a powder of the active ingredient (i.e., the therapeutic compound) plus any additional desired ingredient from a previously sterile-filtered solution thereof. 
     The actual dosage amount of the one or more therapeutic compounds administered to a subject may be determined by physical and physiological factors such as age, sex, body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the subject and on the route of administration. These factors may be determined by a skilled artisan. The practitioner responsible for administration will typically determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject. 
     In one embodiment, a human subject is administered the daily doses of one or more therapeutic compounds disclosed herein from about 0.01 mg/kg to about 100 mg/kg. 
     Single or multiple doses of the one or more therapeutic compounds disclosed herein are contemplated. Desired time intervals for delivery of multiple doses can be determined by one of ordinary skill in the art employing no more than routine experimentation. As an example, subjects may be administered two doses daily at approximately 12 hour intervals. In some embodiments, the compound is administered once a day. 
     The one or more therapeutic compounds disclosed herein may be administered on a routine schedule. As used herein a routine schedule refers to a predetermined designated period of time. The routine schedule may encompass periods of time which are identical or which differ in length, as long as the schedule is predetermined. For instance, the routine schedule may involve administration twice a day, every day, every two days, every three days, every four days, every five days, every six days, a weekly basis, a monthly basis or any set number of days or weeks there-between. Alternatively, the predetermined routine schedule may involve administration on a twice daily basis for the first week, followed by a daily basis for several months. In other embodiments, the invention provides that one or more therapeutic compounds disclosed herein may be taken orally and that the timing of which is or is not dependent upon food intake. Thus, for example, the one or more therapeutic compounds disclosed herein can be taken every morning and/or every evening, regardless of when the subject has eaten or will eat. 
     Combination Therapy 
     In addition to being used as a monotherapy, the one or more therapeutic compounds disclosed herein or pharmaceutical compositions thereof may also find use in combination therapies. Effective combination therapy may be achieved with a single pharmaceutical composition or pharmacological formulation that includes both agents, or with two distinct pharmaceutical compositions or pharmacological formulations, administered at the same time, wherein one composition includes one or more therapeutic compounds disclosed herein, and the other includes the second agent(s). Alternatively, the therapy may precede or follow the other agent treatment by intervals ranging from minutes to months. 
     The additional agent or agents may be selected from any agent or agents useful for treating a psychological disorder, for example any agent or agent and/or α2s useful for treating an imbalance of dopamine, serotonin, histamine, or glutamate. In one embodiment, the additional agent or agents are useful in improving psychological function, e.g., an antipsychotic, such as quetiapine, geodon, zyprexa, latuda, olanzapine, risperidone, iloperidone, ziprasidone, clozapine, haloperidol, chlorpromazine, citalopram, escitalopram, paroxetine, fluoxetine, fluvoxamine, sertraline, desvenlafaxine, duloxetine, milnacipran, venlafaxine, vilazodone, and combinations thereof. 
     Synthesis of the Amisulpride Derivatives 
     The amisulpride derivatives disclosed herein of the present invention can be prepared from amisulpride (4-amino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide), which is readily available. The synthesis of amisulpride is described, for example, in U.S. Pat. No. 4,401,822. 
     The following synthesis for preparing the compounds of formula IB can be adapted to prepare other compounds of the present invention, such as compounds of Formulas I, IA and IC. The compound of formula IB can be prepared by (a) treating amisulpride with a mixture of a carboxylic acid and its corresponding anhydride to obtain the corresponding amide, (b) reduction of the amide to the amine with a suitable reducing agent, for example, borane:dimethyl sulfide to form a compound of Formula IB: 
     
       
         
         
             
             
         
       
         
         
           
             wherein Z is defined the same as above, and Z=—C—R. 
           
         
       
    
     This reaction scheme is shown below: 
     
       
         
         
             
             
         
       
     
     Similarly, compounds of Formula IA can be prepared by further substituting the N—H in the corresponding compound of Formula IB with the corresponding X group; and compounds of Formula IC can be prepared by acylation of the aniline nitrogen in the corresponding compound of Formula IB followed by reduction. 
     Additionally, 4-methylamino substituted amisulpride derivatives may be prepared by reacting amisulpride with N,N-dimethylformamide dimethyl acetal to provide the corresponding amide, which is then reduced by a reducing agent (e.g., NaBH 4 , DMS:BH 3 , Red-Al, and LiAlH 4 ) to provide the corresponding 4-methylamino substituted amisulpride derivatives. 
     
       
         
         
             
             
         
       
     
     Stereoisomers of the amisulpride derivatives disclosed herein can be prepared similarly by using the corresponding stereoisomer of amisulpride as the starting material. For example, synthesis of ((S)-4-amino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide can be carried out as described in U.S. Pat. No. 6,169,094, which is incorporated herein by reference. The S isomers of the amisulpride derivatives can be prepared using the S isomer of amisulpride (Schemes 3 and 4). The R isomers of the amisulpride derivatives can be similarly prepared using the R isomer of amisulpride. 
     
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
     
     When neither Z or X of an amisulpride derivative of Formula I is hydrogen, the amisulpride derivative (di-substituted 4-amino amisulpride derivative) may be prepared by a two-step substitution of the 4-amino group. First, the 4-amino group is substituted with a first substitution group of Z or X as shown above to provide a mono-substituted 4-amino amisulpride derivative; and then the mono-substituted 4-amino amisulpride derivative is further substituted with a second substitution at the 4-amino to provide the desired di-substituted 4-amino amisulpride derivative. See, e.g., Examples 3C and 3D. 
     Having described the invention with reference to the embodiments and illustrative examples, those in the art may appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications. Further, all references cited above and in the examples below are hereby incorporated by reference in their entirety, as if fully set forth herein. 
     EXAMPLES 
     Example 1: Synthesis of 4-formylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (Compound 1) 
     
       
         
         
             
             
         
       
     
     To a solution of 4-amino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (2 g, 5.5 mmol) in 20 mL formic acid, acetic anhydride (0.68 g, 6.6 mmol) was added portionwise at 5-10° C. The reaction mixture was stirred overnight at room temperature, and carefully poured into aq. K 2 CO 3  at 5-10° C. Solid NaCl was added and the mixture was extracted with CHCl 3 . The combined organic extracts were dried over Na 2 SO 4 , and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 5-10% MeOH in CHCl 3  to afford 1.82 g (83%) of a yellowish gum.  1 H NMR (400 MHz, CDCl 3 ): δ 1.1 (t, 3H, CH 3 ), 1.3 (t, 3H, CH 3 ) 1.6 (br s, 2H), 1.7 (br s, 2H), 1.9 (br s, 1H), 2.3 (br s, 2H), 2.7 (br s, 1H), 2.9 (br s, 1H), 3.2 (q, 2H), 3.3 (br s, 1H), 3.4 (br s, 1H), 3.7 (m, 1H), 4.1 (s, 3H, OCH 3 ), 8.4 (br s, 1H, NH), 8.5 (s, 1H, H ar ), 8.6 (s, 1H, H ar ), 8.7 (s, 1H, CHO), 10.1 (s, 1H, NH). Expected Mol. Wt. [C 18 H 27 N 3 O 5 S]: 397.2, Observed Mol. Wt. 398.1 [M+H + ]. 
     Example 2: Synthesis of 4-methylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (Compound 102) 
     
       
         
         
             
             
         
       
     
     To a solution of 4-formylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (Compound 1, 1.82 g, 4.6 mmol) in 80 mL THF, BH 3 .Me 2 S (1.09 mL, 11.5 mmol) was added portionwise at 5-10° C. The reaction mixture was stirred at 60° C. for 3 h, and carefully quenched with MeOH (40 mL). The reaction mixture was acidified with 10% HCl (15 mL) and the mixture was stirred at 60° C. overnight. The solvents were evaporated under reduced pressure, the aqueous residue was diluted with H 2 O and basified with aq NaOH to pH 10. The mixture was extracted with CHCl 3 , the combined organic extracts were dried over Na 2 SO 4  and evaporated. The residue was purified by column chromatography on silica gel eluting with 5-10% MeOH in CHCl 3 , following by purification by RP-HPLC eluting with a gradient MeCN—H 2 O+0.1% TFA. The fractions containing the target material were partially evaporated under reduced pressure, basified with aq NaOH to pH 10, and extracted with CH 2 Cl 2 . The combined extracts were dried with Na 2 SO 4  and evaporated under reduced pressure to afford the product as a white solid after standing which solidified upon storage (0.93 g, 53%).  1 H NMR (400 MHz, CDCl 3 ): δ 1.1 (t, 3H, CH 3 ), 1.3 (t, 3H, CH 3 ), 1.6 (m, 3H), 1.9 (m, 1H), 2.2 (m, 2H), 2.5 (m, 1H), 2.7 (m, 1H), 2.9 (app d, 3H, NHCH 3 ), 3.1 (q, 2H, CH 2 ), 3.2 (m, 1H), 3.3 (m, 1H), 3.6 (m, 1H), 4.0 (5, 3H, OCH 3 ), 6.1 (5, 1H, H ar ), 6.8 (br s, 1H, H ar ), 8.1 (br s, NH), 8.5 (s, 1H, NH).  13 C NMR (75 MHz, CDCl 3 ): δ 8.2, 14.9, 21.2, 29.0, 29.9, 40.5, 47.8, 49.5, 53.7, 56.9, 61.0, 92.1, 110.2, 111.9, 136.1, 150.0, 162.2, 164.0. Expected Mol. Wt. [C 18 H 29 N 3 O 4 S]: 383.2, Observed Mol. Wt. 384.5 [M+H + ]. 
     Example 3: Synthesis of Stereoisomers (Compounds 103 and 104) of Compound 102, and 4-amino Amisulpride Derivatives (Compounds 105 to 110) 
     A): Synthesis of ((S)-4-methylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (Compound 103) 
     ((S)-4-amino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (11.1 g) was suspended in N,N-dimethylformamide dimethyl acetal (33 mL) and stirred for 2 hours at 90° C. The reaction mixture was cooled to room temperature and NaBH 4  (4 g) was added portionwise. The mixture was stirred at room temperature for 1 h. Saturated NaCHO 3  (50 mL) was added to quench the reaction, and the resulting suspension was extracted with dichloromethane (2×50 mL). The organic phase was washed with brine, dried, filtered, and the solvent removed under reduced pressure. The residue was purified by column chromatography, eluting with CH 2 Cl 2 /MeOH/NH 3 , to afford the product as a white solid that was further purified by recrystallization from acetone (5.3 g). 
       1 H NMR (400 MHz, DMSO-d 6 ): δ 1.1 (2t, 2×3H, CH 3 ), 1.5 (2, 1H) 1.6 (m, 2H), 1.8 (m, 1H), 2.1 (m, 1H), 2.3 (m, 2H), 2.5 (t, 1H), 2.6 (m, 1H), 2.7 (m, 1H), 2.9 (t, 3H), 3.1 (3, 2H), 3.2 (m, 2H), 3.3 (m, 3H), 3.5 (m, 1H), 4.0 (5, 3H, OCH3), 6.3 (5, 1H ar ), 6.6 (m, 1H ar ), 8.1 (m, 1H, NH), 8.3 (5, 1H, NH).  13 C NMR (100 MHz, DMSO-d 6 ): δ 7.56, 14.51, 23.05, 28.54, 30.39, 41.64, 47.90, 48.77, 53.62, 56.79, 62.36, 94.45, 109.94, 111.63, 135.68, 151.48, 163.14, 163.82. Expected Mol. Wt. [C 18 H 27 N 3 O 4 S] 383.2, Observed Mol. Wt. 384.4 [M+H + ]. 
     B): Synthesis of ((R)-4-methylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (Compound 104) 
     ((R)-4-amino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (11.2 g) was suspended in N,N-dimethylformamide dimethyl acetal (33 mL) and stirred for 2 hours at 90° C. The temperature was reduced to 70° C. and NaBH 4  (4 g) was added in 1 g portions at intervals of 20 minutes. After completion of the addition, the reaction mixture was left to stir a further hour at 90° C. The reaction mixture was cooled in an ice bath and the reaction quenched by addition of 150 mL of saturated NaHCO 3 . The resulting solution was extracted with CH 2 Cl 2  (5×50 mL) and the combined organic extracts dried over Na 2 SO 4 . Purification was achieved by column chromatograpy, eluting with 10% MeOH/CH 2 Cl 2  to afford 7.9 g of a white solid. 
       1 H NMR (300 MHz, CDCl 3 ): δ 1.2 (t, 3H, CH 3 ), 1.3 (t, 3H, CH 3 ), 1.7 (m, 1H) 1.8 (m, 2H), 1.9 (m, 1H), 2.3 (m, 2H), 2.7 (m, 1H), 2.9 (m, 1H), 2.9 (d, 1H), 3.1 (q, 2H), 3.3 (m, 2H), 3.7 (m, 1H), 4.0 (s, 3H, OCH 3 ), 6.1 (s, 1H ar ), 6.8 (m, 1H ar ), 8.1 (m, 1H, NH), 8.6 (s, 1H, NH). Expected Mol. Wt. [C 18 H 27 N 3 O 4 S] 383.2, Observed Mol. Wt. 384.2 [M+H + ]. 
     C): Synthesis of (4-dimethylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (Compound 105) 
     4-methylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (500 mg) was stirred in 10 mL formic acid at 30° C. for 21 h as NaBH 4  (8 equiv) was added in two portions and washed with aqueous NaOH to afford 408 mg of compound 105. 
       1 H NMR (400 MHz, CDCl 3 ): δ 1.2 (t, 3H, CH 3 s), 1.7 (m, 1H), 1.8 (m, 2H), 1.9 (m, 1H), 2.2 (m, 2H), 2.7 (m, 1H), 3.2 (m, 1H), 3.3 (m, 1H), 3.4 (q, 2H), 4.0 (s, 3H, OCH 3 ), 6.8 (5, 1H ar ), 8.0 (5, 1H, NH) 8.8 (5, 1H).  13 C NMR (100 MHz, CDCl 3 ): δ 7.38, 14.21, 22.96, 28.40, 41.24, 46.14, 48.39, 53.66, 56.11, 62.19, 104.94, 118.52, 126.17, 136.07, 157.93, 161.56, 163.79. Expected Mol. Wt. [C 19 H 31 N 3 O 4 S] 397.2, Observed Mol. Wt. 398.2 [M+H + ]. 
     D): Synthesis of (4-ethylmethylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (Compound 106) 
     4-methylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (500 mg) was stirred in 6 mL 1,2-dichlororethane and sodium triacetoxyborohydride (1 g) and acetaldehyde (219 uL) were added and stirred at room temperature for 17 hours. The reaction was quenched by addition of aqueous NaOH and the product extracted into dichloromethane and purified by column chromatography to afford 98 mg of compound 106. 
       1 H NMR (400 MHz, CDCl 3 ): δ 1.2 (m, 6H, 2 CH 3 s), 1.6 (m, 1H), 1.7 (m, 2H), 1.9 (m, 1H), 2.2 (m, 2H), 2.6 (m, 1H), 2.9 (m, 1H), 3.1 (q, 1H), 3.3 (m, 2H), 3.5 (q, 1H), 3.8 (m, 1H) 4.0 (s, 3H, OCH 3 ), 6.8 (s, 1H ar ), 8.0 (s, 1H, NH) 8.8 (s, 1H).  13 C NMR (100 MHz, CDCl 3 ): δ 7.36, 12.84, 23.00, 28.42, 41.27, 42.99, 48.12, 52.30, 53.70, 56.16. 106.05, 126.41, 130.05, 142.41, 157.554, 157.54, 161.48, 163.90. Expected Mol. Wt. [C 20 H 33 N 3 O 4 S] 411.3, Observed Mol. Wt. 412.3 [M+H + ]. 
     E): Synthesis of (4-ethylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (Compound 107) 
     (Ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (500 mg) was stirred in 6 mL 1,2-dichloroethane with 0.4 mL acetic acid. The mixture was cooled on an ice bath and 1.15 g sodium triacetoxyborohydride was added. The mixture was stirred at room temperature overnight. The reaction was quenched by addition of aqueous NaOH and the product extracted into dichloromethane and purified by column chromatography and recrystallized from acetone/MTBE to afford 309 mg of compound 107. 
       1 H NMR (400 MHz, CDCl 3 ): δ 1.1 (br t, 3H, CH 3 ), 1.3 (t, 3H, CH 3 ), 1.4 (t, 3H, CH 3 ), 1.5-1.8 (m, 5H), 1.8 (m, 1H), 2.2 (m, 2H), 2.7 (m, 1H), 2.9 (m, 1H), 3.1 (q, 2H), 3.3 (m 2H), 3.7 (m, 1H), 4.0 (s, 3H, OCH 3 ), 6.1 (s, 1H ar ), 6.7 (s, 1H ar ), 8.1 (s, 1H, NH) 8.6 (5, 1H).  13 C NMR (100 MHz, CDCl 3 ): δ 7.34, 14.17, 22.96, 28.47, 37.99, 41.35, 48.00, 49.82, 53.70, 55.80, 62.38, 93.35, 110.89, 111.91, 136.76, 150.76, 162.90, 164.29. Expected Mol. Wt. [C 19 H 31 N 3 O 4 S] 397.2, Observed Mol. Wt. 398.2 [M+H + ]. 
     F): Synthesis of (4-isopropylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (Compound 108) 
     (Ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (500 mg) was stirred in 6 mL DMF with 0.12 mL acetone. The mixture was cooled on an ice bath and 0.3 mL TFA was added followed by addition of 441 mg sodium triacetoxyborohydride. The mixture was stirred at 40° C. overnight. The reaction mixture was poured into aqueous NaOH and the product extracted into dichloromethane and purified by column chromatography to afford 550 mg of compound 108. 
       1 H NMR (400 MHz, CDCl 3 ): δ 1.1 (br t, 3H, CH 3 ), 1.2 (t, 3H, CH3), 1.3 (t, 6H, CH 3 ), 1.6 (m, 2H), 1.7 (m, 2H), 1.9 (m, 1H), 2.2 (m, 1H), 2.6 (m, 1H), 2.9 (m, 1H), 2.1 (q, 2H), 3.2 (m, 2H), 3.7 (m, 1H), 4.0 (s, 3H, OCH 3 ), 6.1 (s, 1H ar ), 6.7 (s, 1H ar ), 8.0 (s, 1H, NH) 8.6 (5, 1H).  13 C NMR (100 MHz, CDCl 3 ): δ 7.36, 22.45, 23.02, 28.48, 41.35, 44.15, 49.95, 53.74, 55.80, 93.65, 111.83, 136.69, 150.03, 162.87, 164.33. Expected Mol. Wt. [C 20 H 33 N 3 O 4 S] 411.2, Observed Mol. Wt. 412.2 [M+H + ]. 
     G): Synthesis of (4-n-propylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (Compound 109) 
     (Ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (500 mg) was stirred in 6 mL 1,2-dichloroethane with 0.3 mL proprionaldehyde. Sodium triacetoxyborohydride (1.2 g) was added in two portions 10 minutes apart, and the mixture was left to stir overnight. The reaction mixture was poured into aqueous NaOH and the product extracted into ethyl acetate and purified by column chromatography to afford 518 mg of compound 109. 
       1 H NMR (400 MHz, CDCl 3 ): δ 1.1 (br t, 3H, CH 3 ), 1.2 (t, 3H, CH 3 ), 1.3 (t, 6H, CH 3 ), 1.6 (m, 2H), 1.7 (m, 2H), 1.9 (m, 1H), 2.2 (m, 1H), 2.6 (m, 1H), 2.9 (m, 1H), 2.1 (q, 2H), 3.2 (m, 2H), 3.7 (m, 1H), 4.0 (s, 3H, OCH 3 ), 6.1 (s, 1H ar ), 6.7 (s, 1H ar ), 8.0 (s, 1H, NH) 8.6 (5, 1H).  13 C NMR (100 MHz, CDCl 3 ): δ 7.36, 22.45, 23.02, 28.48, 41.35, 44.15, 49.95, 53.74, 55.80, 93.65, 111.83, 136.69, 150.03, 162.87, 164.33. Expected Mol. Wt. [C 20 H 33 N 3 O 4 S] 411.2, Observed Mol. Wt. 412.2 [M+H + ]. 
     H): Synthesis of (4-benylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (Compound 110) 
     (Ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (500 mg) was stirred in 7 mL DMF with 1.25 mL benzaldehyde and 1 mL TFA. Sodium triacetoxyborohydride (3.5 g) was added in two portions, and the mixture was left to stir overnight at 40° C. The reaction mixture was poured into aqueous NaOH and the product extracted into dichloromethane and purified by column chromatography to afford 366 mg of compound 110. 
       1 H NMR (400 MHz, CDCl 3 ): δ 1.2 (t, 3H, CH 3 ), 1.2-1.3 (3, 3H,), 1.5-1.8 (m, 3H), 1.8-2.0 (m, 1H), 2.3 (m, 2H), 2.6 (br s, 1H), 2.9 (m, 1H), 3.1-3.3 (m, 1H), 3.7 (m, 1H), 3.8 (s, 3H), 4.5 (br s, 2H), 3.7 (m, 1H), 4.0 (s, 3H, OCH 3 ), 6.1 (s, 1H ar ), 7.4 (m, 5H), 8.0 (5, 1H, NH) 8.6 (5, 1H).  13 C NMR (100 MHz, CDCl 3 ): δ 7.36, 14.20, 22.91, 28.5, 41.32, 47.52, 50.03, 53.65, 55.77, 62.32, 94.62, 111.36, 112.24, 126.95, 128.97, 136.59, 137.43, 150.53, 162.69, 1664.15. Expected Mol. Wt. [C 24 H 33 N 3 O 4 S] 459.2, Observed Mol. Wt. 460.2 [M+H + ]. 
     Example 4: Membrane Permeability of Compound 102 
     Membrane permeability of 4-methylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide) (Compound 102) was measured using a PAMPA assay at pH 5 and 7.4. Specifically, 10 mM solutions of controls ranitidine (3.5 mg in 1 mL DMSO) and propanolol (2.9 mg in 1 mL DMSO), N-methyl amisulpride (3.3 mg in 0.8 mL DMSO), and amisulpride (3.4 mg in 0.9 mL DMSO) were prepared. Diffusion across a Pion PAMPA membrane were measured at pH 5 and pH 7.4, as shown in Table 1, respectively 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Permeability of Compound 102, amisulpride, propanolol, and 
               
               
                 ranitidine through a PAMPA membrane at pH 5 and 7.4. 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Permeability 
                 Permeability 
               
               
                   
                 Test Compound 
                 (cm/s) pH 5 
                 (cm/s) pH 7.4 
               
               
                   
               
               
                   
                 Amisulpride 
                 2.4 × 10 −10   
                 2.4 × 10 −11   
               
               
                   
                 N-methyl amisulpride 
                 2.1 × 10 −8   
                 5.2 × 10 −9   
               
               
                   
                 (Compound 102) 
                   
                   
               
               
                   
                 Propanolol 
                 3.1 × 10 −8   
                 7.8 × 10 −6   
               
               
                   
                 Ranitidine 
                 1.1 × 10 −10   
                 1.5 × 10 −10   
               
               
                   
               
            
           
         
       
     
     Example 5: Binding of Compound 102 to Dopamine D 2  Receptors (Cell-Based Assay) 
     The ability of Compound 102 to bind dopamine D 2  receptors was measured in a cell-based assay. Dopamine D 2  receptor cells were seeded in a half a black, clear-bottomed 96 well plate. At a density of 15,000 cells/well to a volume of 25 μL and were left to incubate overnight. Calcium 5 dye in HEPES buffered HBSS (Hanks&#39; balanced salt solution) was prepared and 10 μL was added to each well and the mixture was left to sit at 37° C. for 1 hour. After equilibration, 5 μL of the test compound and controls were added to the wells and incubated at room temperature for 10 minutes. Fluorescence was measured every 1.52 seconds. After 20 seconds 10 μL of dopamine (at EC 80  concentration) was added and the fluorescence monitored for 2 minutes with excitation at 452 nm and emission at 525 nm. Cell-based IC 50  values for Compound 102, together with known dopamine D 2  inhibitors risperidone, amisulpride, and clozapine are presented in Table 2. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 IC 50  values for Compound 102, risperidone, amisulpride, and 
               
               
                 clozapine against dopamine D2 receptors (cell-based assay). 
               
            
           
           
               
               
               
            
               
                   
                 Compound 
                 D 2  IC 50  nM 
               
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Compound 102 
                 8.9 
               
               
                   
                 Risperidone 
                 3.6 
               
               
                   
                 Amisulpride 
                 1.5 
               
               
                   
                 Clozapine 
                 7100 
               
               
                   
               
            
           
         
       
     
     Example 6: Binding of Compound 102 to Dopamine D 2  Receptors (membrane Preparation) 
     The ability of Compound 102 to bind the dopamine D 2  receptor in a membrane preparation was examined. Medium was removed from dopamine D 2  receptor cells and washed with PBS. A lysis buffer (250 mM sucrose, 1 nM EDTA, 10 mM Tris HCl buffered at pH 7.2 plus protease inhibitors) was added and cells scrapped using a plate scrapper. Cells were homogenized with 20 manual up and down strokes in a glass homogenizer. Intact cells, nuclei, and cell debris were removed by centrifugation of the homogenate at 500×g for 10 minutes at 4° C., the supernatant was removed, and the pellet resuspended in assay buffer. 
     Membrane preparations were incubated with  3 H spiperone until equilibration. Separation of bound from free radioligand was carried out using a Packard Filtermate Harvester and glass filter plates. Radioactivity was measured using a Packard Topcount. To 20 μL of D 2  membranes were mixed 20 μL of  3 H spiperone and 10 μL test compound or reference ligand in binding buffer in a nonbinding 96 well plate, and incubated for &lt;120 minutes. Prior to filtration, a 96 well harvest filter plate was coated with 0.33% polyethyleneimine for 30 minutes and then washed with assay buffer. The binding reaction was transferred to the filter plate and washed three times with wash buffer, dried, scintillant added, and radioactivity counted on a Topcount NXT. 
     Compound 102, risperidone, amisulpride, and clozapine were tested using 0.1 nM  3 H spiperone at concentrations of 1000, 100, 10, 1, 0.1, and 0.01 nM in triplicate. IC 50  values for this membrane based assay are presented in Table 3. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 IC 50  values for Compound 102, risperidone, amisulpride, and 
               
               
                 clozapine against dopamine D 2  receptors (membrane based assay). 
               
            
           
           
               
               
               
            
               
                   
                 Compound 
                 D 2  IC 50  nM 
               
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Compound 102 
                 8.2 
               
               
                   
                 Risperidone 
                 10.4 
               
               
                   
                 Amisulpride 
                 8.5 
               
               
                   
                 Clozapine 
                 2800 
               
               
                   
               
            
           
         
       
     
     Example 7: Binding of Compound 102 and Compound 103 to Various CNS Receptors (Dopamine D 2 , Dopamine D 3 , α2 Adrenergic, and 5-HT 2a  Receptors) (Table 4) 
     The ability of Compound 102 and 103 to bind α 2  (non-selective), α2A, α2B, α2c, 5-HT 2A  (agonist), 5-HT 2A  (antagonist), D 2L , D 2S es, and D 3  was measured at concentrations ranging from 10×10 −5  to 10×10 −9  M and measuring displacement of reference ligands (prazosin for α2 (non-selective), yohimbine for α2A, α2B and α2c, DOI ([2,5-dimethoxy-4-iodophenyl]-2-aminopropane) for 5-HT 2A  (agonist), ketanserine for 5-HT 2A  (antagonist), butaclamol for D 2L , 7-OH-DPAT for D 2S , and (+) blutaclamol for D 3 ). bound to the respective isolated receptor. Inhibition data are reported in Table 4. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 IC 50  and K i  values for Compounds 102 (LB102) and Compound 103 
               
               
                 (LB103) against various CNS receptors in a cell based assay. 
               
            
           
           
               
               
               
               
               
            
               
                   
                 IC50 (nM) 
                   
                 Ki (nM) 
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 LB102 
                 LB103 
                 LB102 
                 LB103 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 α- 2A  (non-selective) 
                 95 
                 150 
                 41 
                 6.7 
               
               
                 α- 2A  (h) 
                 480 
                   
                 220 
                   
               
               
                 α- 2B  (h) 
                 170 
                   
                 110 
                   
               
               
                 α- 2C  (h) 
                 790 
                   
                 240 
                   
               
               
                 5-HT 2A  (agonist) 
                 270 
                 550 
                 200 
                 410 
               
               
                 5-HT 2A  (antagonist) 
                 890 
                 980 
                 490 
                 530 
               
               
                 5-HT 7   
                 74 
                   
                 27 
                   
               
               
                 D2L 
                 2.7 
                 1.7 
                 0.66 
                 0.41 
               
               
                 D2S 
                 8.4 
                 1.4 
                 3.4 
                 0.56 
               
               
                 D3 
                 11 
                 5.5 
                 2.5 
                 1.2 
               
               
                   
               
            
           
         
       
     
     Example 8: Novel Object Recognition (NOR) Assay Showed Efficacies of Compounds 102 and 103 
     Efficacy of Compounds 102 and 103 was evaluated in rats in a Novel Object Recognition (NOR) assay, a well-established model recapitulating cognitive and negative aspects of the PANSS scale of schizophrenia. In this assay, animals were treated for several weeks with a low dose of phencyclidine (PCP) to impair the ability of the rat to discern between novel and familiar objects. Typically rats, like humans, would spend more time exploring a novel object than a familiar one. The efficacy in this study was demonstrated by the ability of the test treatment to restore normal brain function as manifested by reversing the PCP impairment. 
     In this NOR study the efficacy of Compounds 102 and 103 was compared to known antipsychotics amisulpride and risperidone for its ability to restore normal differentiation between novel and familiar object exploration in PCP-treated rats. Rats (n=10/group) were dosed with 2 mg/kg intraperitoneal twice a day (i.p., b.i.d.) for seven days followed by 7 days drug free. Cognitive measurements, at various PO doses test agent, were taken at 3 hours post-dose for Compound 102, 103, and amisulpride and at 30 minutes for risperidone. Novel object exploration time was measured for the test subjects from a sub-chronic PCP NOR study in rats (n=10/group). The differences in exploration time between novel (Tnovel¬) and familiar (Tfamliar) objects are depicted in  FIG. 1A  (*: p&lt;0.05; and **: p&lt;0.01).  FIG. 1B  shows discrimination index of the NOR study obtained by the following Equation 1:
 
Discrimination index=(time spent exploring novel−time spent exploring familiar)/total exploration time)  (Equation 1)
 
       FIGS. 1A and 1B  show that all doses of Compounds 102 and 103, save one, increased the difference between novel and familiar object exploration time in a manner consistent with currently used antipsychotics amisulpride and risperidone. 
     In the NOR study depicted in  FIGS. 1A and 1B , Compounds 102 and 103 were able to restore known object exploration behavior in rats treated with PCP to levels similar to untreated rats, and on par with values obtained using known antipsychotics Amisulpride and Risperidone. 
     Example 9: Amphetamine-Induced Locomotor Activity (LMA) Assay Showed Efficacies of Compounds 102 and 103 
     Efficacy of Compounds 102 and 103 was studied in rats in an amphetamine-induced Locomotor Activity (LMA) assay, a measure of positive aspects of the PANSS scale. In the LMA assay rats were dosed with amphetamine (Amp, 1 mg/kg, s.c.), causing excessive movement, in a cage with sensors that monitored how far each rat moved. Rats dosed with amphetamine alone tended to show hypermobility while rats dosed with antipsychotics showed more normal, calmer, activity. 
     In this LMA study Compounds 102 (Cpd 102, 30 mg/kg) and 103 (Cpd 103, 30 mg/kg), amisulpride (30 mg/kg), and risperidone (1 mg/kg) were dosed orally in groups of 10 rats. Distance moved, over the course of an hour, was measured 6 hours post dosing for Compounds 102 and 103 and amisulpride—risperidone was dosed 1 hour prior to measurement. The endpoint of this study was total ambulatory distance (the distance traveled by each animal in the cage). Total ambulatory distance data from this amphetamine induced LMA study are summarized in  FIG. 2  (*:p&lt;0.01; **: p&lt;0.05). 
     In this LMA study in rats, as shown in  FIG. 2 , the normalized amphetamine hyperactivity of Compound 102 was statistically superior to that of amisulpride (p&lt;0.05), and the normalized amphetamine hyperactivity of Compound 103 was statistically indistinguishable from that of amisulpride (p&lt;0.01). 
     Example 10: Binding of Compounds 102, 103, and 104 to 5HT 7  Receptors 
     The ability of Compounds 102, 103, and 104 to bind 5-HT 7  was measured at concentrations ranging from 1×10 −7  to 3×10 −10  M and measuring displacement of a calcium sensitive fluorescent indicator in cells expressing 5-HT 7 . Using this assay, the K i  of Compound 102 (LB-102, solid filled circle, Plot B,  FIG. 3 ) was found to be 31±1.0 nM, compared to 44 nM for amisulpride (LB-101, solid filled circle, Plot A,  FIG. 3 ). Unexpectedly given that Compound 103 (the S enantiomer of Compound 102) was a stronger binder than Compound 104 (the R enantiomer of Compound 102) to the dopamine receptors, binding of the Compound 104 (the R enantiomer of Compound 102) afforded a K i  of 15.6±0.9 nM (LB-104, solid filled circle, Plot D,  FIG. 3 ) compared to a K i  of &gt;1,000 nM for Compound 103 (S enantiomer of Compound 102) (LB-103, solid triangle, Plot C,  FIG. 3 ). Unexpectedly, the R enantiomer of amisulpride (Ami(r), solid circle, Plot A,  FIG. 4 ) showed a lower K i  (21.8±1.5 nM) than the S enantiomer of amisulpride (K i =900±1300 nM) (Ami(s), solid circle, Plot C,  FIG. 4 ). The amisulpride racemic mixture (Ami(rac), solid circle, Plot B,  FIG. 4 ) had a K i  (44 nM) higher than that of the R enantiomer of amisulpride but lower than that of the S enantiomer of amisulpride. 
     Example 11: Binding of Compounds 102, 103, and 104 to D 2  Receptor 
     The abilities of Compounds 101, 102, 103, and 104 to bind D 2  receptor were conducted on a GPCR screening platform. In short, the assays were ligand displacement based. The apparent affinity of the natural ligand dopamine for the D 2  receptor were examined in the presence of increasing concentrations of benzamide antagonists. The apparent affinity constants (EC 50 ) of the ligands were determined by the 4-parameter response equation (Equation 2 below):
 
(Max−Min)/(1+(EC 50 /[Ligand]){circumflex over ( )} n )+Min  (Equation 2)
 
wherein:
         Max is the signal at saturating ligand (dopamine or serotonin);   Min is the signal in the absence of ligand (or at saturating antagonist);   EC 50  is the concentration of ligand producing ½ the maximum signal; and   n is the Hill coefficient.       

     Antagonist dissociation constant K(D A) and ligand dissociation constant K(D L) were determined from global fits of the EC 50 &#39;s v antagonist concentration using the Cheng-Prusoff competitive ligand relationship (Equation 3 below):
 
EC 50   =K ( DL )*(1+[ A ]/ K ( DA ))  (Equation 3)
 
     When enantiomeric systems were examined (enantiomerically pure R enantiomer, enantiomerically pure S enantiomer, and racemate) the global fits were as follows (Equations 4-6):
 
EC 50   =K ( DL )*(1+[ A ( s )]/ K ( DA ( s )))  (Equation 4 for enantiomerically pure S enantiomer)
 
EC 50   =K ( DL )*(1+[ A ( r )]/ K ( DA ( s )))  (Equation 5 for enantiomerically pure R enantiomer)
 
EC 50   =K ( DL )*(1+0.5*[ A (rac)]/ K ( DA ( s )+0.5*[ A (rac)]/ K ( DA ( r )))  (Equation 6 for racemate)
 
     As shown in  FIGS. 5A and 5B  for D 2  binding, LB-103 bound D 2  with a K i  (0.4±0.04 nM) lower than those of LB-102 or LB-104; LB-104 had a higher K i  (14.4±2.2 nM) than LB-102 (0.82±0.02 nm); and LB-101 had a K i  (1.1±0.12 nm) higher than LB-102 and LB-103 but lower than LB-104. 
     REFERENCES 
     The references listed below, and all references cited in the specification are hereby incorporated by reference in their entireties, as if fully set forth herein.
     1) H. Y. Meltzer and S. S. Stahl, “The Dopamine Hypothesis of Schizophrenia—A Review,” Schizophr. Bull., 1976, 2, 19-76.   2) J. J. Joyce and J. H. Meador-Woodruff, “Linking the Family of D2 Receptors to Neuronal Circuits in Human Brain: Insights into Schizophrenia,” Neuropsychopharmacology, 1997, 16, 1444-1449.   3) S. Wulff, L. Hageman Pinborg, C. Svarer, L. Thorbjørn Jensen, M. Ødegaard Nielsen, P. Allerup, N. Bak, H. Rasmussen, E. Frandsen, E. Rostrup, and B. Yding Glenthøj, “Striatal D2/3 Binding Potential Values in Drug-Naïve First-Episode Schizophrenia Patients Correlate with Treatment Outcome,” Schizophrenia Bulletin, 2015, 41, 1143-1152.   4) B. L. Roth, D. J. Sheffler, and W. K. Kroeze, “Magic Shotguns Versus Magic Bullets: Selectively Non-Selective Drugs for Mood Disorders and Schizophrenia,” Nature Reviews Drug Discovery, 2004, 3, 353-359.   5) M. Thominet, J. Acher, and J.-C. Monier, “Derivatives of 4-Amino-5-Alkyl Sulphonyl Orthoamides,” U.S. Pat. No. 4,401,822, Filed Oct. 9, 1981 (Issued Aug. 30, 1983).   6) H. Shoemaker, Y. Claustre, D. Fage, L. Rouquier, K. Chergui, O. Curet, A. Oblin, F. Gonon, J. Benavides, and B. Scatton, “Neurochemical Characteristics of Amisulpride, An Atypical Dopamine D2/D3Receptor Antagonist with Both Presynaptic and Limbic Selectivity,” J. Pharmacol. Exp. Ther., 1997, 280, 83-97.   7) A. A. Abbas, P. B. Hedlund, X-P. Huang, T. B. Tran, H. Y. Meltzer, and B. L. Roth, “Amisulpride Is a Potent 5-Ht7 Antagonist: Relevance for Antidepressant Actions In Vivo,” Psychopharmacology, 2009, 119-128.   8) S. Jafari, F. Fernandez-Enright, and X.-F. Huang, “Structural Contributions of Antipsychtoic Drugs to Their Therapeutic Profiles and Metabolic Side Effects,” J. Neurochemistry, 2012, 120, 371-384.   9) J. N. Dos Santos Pereira, S. Tadjerpisheh, M. Abu Abed, A. R. Saadatmand, B. Weksler, I. A. Romero, P.-O. Couraud, J. Brockmöller, and M. V. Tzvetkov, “The Poorly Membrane Permeable Antipsychotic Drugs Amisulpride and Sulpride Are Substrates of the Organic Cation Transporters from the SLC22 Family,” The AAPS Journal, 2014, 16, 1247-1258.   10) J. C. Neill, S. Barnes, S. Cook, B. Grayson, N. F. Idris, S. L. McLean, S. Snigdha, L. Rajagopal, and M. K. Harte, “Animal Models of Cognitive Dysfunction and Negative Symptoms of Schizophrenia: Focus on NMDA Receptor Antagonism,” Pharmacology &amp; Therapeutics, 2010, 128, 419-432.   11) J. C. Neill, M. K. Harte, P. M. Haddad, E. S. Lydall, and D. M. Dwyer, “Acute and Chronic Effects of Nmda Receptor Antagonists in Rodents, Relevance to Negative Symptoms of Schizophrenia: A Translational Link to Humans,” European Neuropsychopharmacology, 2014, 24, 822-835.   12) J. C. Neill, B. Grayson, B. Kiss, I. Gyertyan, P. Ferguson, and N. Adham, “Effects of Cariprazine, A Novel Antipsychotic, On Cognitive Deficit and Negative Symptoms in a Rodent Model of Schizophrenia Symptomatology,” European Neuropsychopharmacology, 2016, 26, 3-14.   13) M. P. Castelli, I. Mocci, A. M. Sanna, G. L. Gessa, L. Pani, “(−)S amisulpride binds with high affinity to cloned dopamine D3 and D2 receptors,” Euro. J. Pharmacol., 2001, 432, 143-147.   14) J. Titulaer, A. Malmerfelt, M. Marcus, T. Svensson, “Rapid augmentation of antipsychotic drugs by sodium nitroprusside (SNP)—behavioural assessment and effect on brain dopaminergic transmission in rats,” European Neuropsychopharmacology, 2017, 27, S922-S923.   15) P. B. Hedlund, “The 5-HT 7  receptor and disorders of the nervous system: an overview,” Psychopharmacology (Berl.), 2009, 206, 345-354.   16) E. Smeraldi, “Amisulpride versus fluoxetine in patients with dysthymia or major depression in partial remission: a double-blind, comparative study,” J. Affect Disord., 1998, 48, 47-56.   17) G. B. Cassano, M. C. Jori, “Efficacy and safety of amisulpride 50 mg versus paroxetine 20 mg in major depression: a randomized, double-blind, parallel group study,” Int. J. Clin. Psychopharmacol., 2002, 17, 27-32.   18) Y. Lecrubier, P. Boyer, S. Turjanski W. Rein, “Amisulpride versus imipramine and placebo in dysthymia and major depression. Amisulpride Study Group,” J. Affective Disorders, 1997, 43, 95-103.   19) A. I. Abbas, P. B. Hedlund, S. P. Huang, T. B. Tran, H. Y. Meltzer, B. L. Roth, “Amisulpride is a potent 5-HT 7  antagonist: relevance for antidepressant actions in vivo,” Psychopharmacology (Berl), 2009, 205, 119.   20) Guscott et al., “Genetic knockout and pharmacological blockade studies of the 5-HT7 receptor suggest therapeutic potential in depression,” Neuropharmacology, 2005, 48, 492-502.   21) A. Wesolowska, A. Nikiforuk, K. Stachowicz, E. Tatarczyńska, “Effect of the selective 5-HT7 receptor antagonist SB 269970 in animal models of anxiety and depression,” Neuropharmacology, 2006, 51, 578-586.