Methods for treating schizophrenia and compositions for use therein

Abstract

A method for treating schizophrenia, which comprises administering to a subject a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, is provided. [Chemical 1] JPEG2025520975000009.jpg58170(wherein X is halogen) A composition for use in a method of treating schizophrenia, which comprises administering to a subject in need thereof a composition comprising a compound of formula (I), (II) or (III) as shown above, is also provided.

Description

Technical Field

[0001] The present disclosure relates to a method for treating schizophrenia and a composition for use in a method for treating schizophrenia.

Background Art

[0002] Schizophrenia is a severe mental illness characterized by a broad range of brain dysfunctions including disturbances in thinking, perception, emotion, language, self-awareness, and behavior. This devastating disorder has a prevalence of about 1% of the population, tends to onset in early adulthood, and may persist throughout the patient's life 1 . Changes in dopaminergic signaling have been associated with schizophrenia and amphetamine intoxication. Hyperdopaminergia is the dominant pathophysiological hypothesis of schizophrenia (i.e., the dopamine hypothesis of schizophrenia). Hyperactive dopaminergic signaling is thought to contribute to the positive symptoms of schizophrenia. Therefore, pharmacological modification of dopamine transmission has been used as a therapeutic means for a long time 2 . Previous positron emission tomography (PET) studies have revealed that dopaminergic function is dysregulated in the prodromal stage of schizophrenia patients and further deteriorates with the onset of psychosis 3 . Risk genes for schizophrenia are associated with upstream and downstream pathways of the dopaminergic system, but none are directly involved in dopamine synthesis and release. The vulnerability of dopaminergic neurons to environmental and developmental risk factors is due to these upstream factors, but the effect of dysregulation is further amplified by downstream factors 4 . To date, antipsychotic drugs that regulate dopamine neurotransmission have continued to be the major class of drugs used to treat schizophrenia 5However, approximately one-third of patients do not respond to dopamine-based antipsychotics. In addition, the use of antipsychotics can result in many undesirable adverse effects such as stiffness, tremors, akathisia, tardive dyskinesia, sexual problems, drowsiness, and weight gain. Moreover, the effectiveness of currently available antipsychotics for treating the negative and cognitive symptoms of schizophrenia is limited. 5 Therefore, it is timely and important to search for new therapeutic targets for mental disorders and to develop new drugs with fewer side effects. SUMMARY OF THE INVENTION

[0003] Based on the above reasons, the present invention provides a new method for treating schizophrenia by using a compound of an adenosine analog to reduce side effects and / or treat schizophrenia-related symptoms, particularly positive symptoms. In one aspect of the present invention, a method for treating schizophrenia, comprising administering to a subject in need thereof a compound of formula (I), (II) or (III), a pharmaceutically acceptable salt thereof, or a composition thereof.

Chemical formula

[0004] In another aspect of the present invention, a composition for use in a method for treating schizophrenia, comprising administering to a subject in need thereof a composition comprising a compound of formula (I), (II) or (III) as shown above. Preferably, the compound is N 6 -[(3-halothien-2-yl)methyl]adenosine, N 6 -[(4-halothien-2-yl)methyl]adenosine, and N 6 -[(5-halothien-2-yl)methyl]adenosine. More preferably, the compound is N 6 -[(5-bromothien-2-yl)methyl]adenosine, N 6 -[(4-bromothien-2-yl)methyl]adenosine, N 6-[(3-Bromothien-2-yl)methyl]adenosine, N 6 -[(5-Chlorothien-2-yl)methyl]adenosine, N 6 -[(4-Chlorothien-2-yl)methyl]adenosine, and N 6 is selected from the group consisting of -[(3-Chlorothien-2-yl)methyl]adenosine. Preferably, the compound is N 6 -[(2-Halothien-3-yl)methyl]adenosine, N 6 -[(4-Halothien-3-yl)methyl]adenosine, and N 6 is selected from the group consisting of -[(5-Halothien-3-yl)methyl]adenosine. More preferably, the compound is N 6 -[(2-Bromothien-3-yl)methyl]adenosine, N 6 -[(4-Bromothien-3-yl)methyl]adenosine, N 6 -[(5-Bromothien-3-yl)methyl]adenosine, N 6 -[(2-Chlorothien-3-yl)methyl]adenosine, N 6 -[(4-Chlorothien-3-yl)methyl]adenosine, and N 6 is selected from the group consisting of -[(5-Chlorothien-3-yl)methyl]adenosine. Preferably, the compound, its pharmaceutically acceptable salt, or its composition is administered by an oral, intravenous, intramuscular, subcutaneous, or intraperitoneal route. Preferably, the composition further comprises a pharmaceutically acceptable carrier, excipient, or vehicle.

[0005] Accordingly, the present invention provides at least the following advantages: 1. The claimed compound is an orally active adenosine analog that can cross the blood-brain barrier. Thus, the method of the present invention can be easily carried out by administering the claimed compound to a subject via the oral route. 2. The claimed invention has the potential to suppress the hyperlocomotor response induced by excessive dopamine.

Brief Description of the Drawings

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[0007] Considering that adenosine and dopamine interact antagonistically in living mammals and that there is an antagonistic interaction between adenosine receptors and dopamine receptors in neurons and astrocytes, the inventors of the present invention investigated whether the regulation of the adenosinergic pathway can modulate the abnormalities of the dopaminergic system in schizophrenia, and proposed that stimulation of the adenosine signaling pathway can indirectly suppress the hyperfunction of dopamine receptors in schizophrenia and alleviate the symptoms of schizophrenia. It is also important to clarify the downstream molecular pathway of the interaction between adenosine and dopamine in order to search for new therapeutic targets.

[0008] Methamphetamine (METH) is a potent dopamine transporter inhibitor that significantly increases extracellular dopamine levels in the brain. METH, a potent psychostimulant, can induce psychosis among recreational and chronic users, and its psychotic syndrome shows similarity to schizophrenia. The overall symptoms of METH-induced psychosis have been described as indistinguishable from those of schizophrenia. Therefore, the present invention examines the molecular crosstalk between dopamine and adenosine receptors in the striatum, which is an important brain region of the dopaminergic pathway and schizophrenia, and aims to evaluate the in vivo efficacy of a novel adenosine analog, which is the claimed compound, in a mouse model of METH-induced psychosis using METH. In one embodiment, there is provided a method for treating schizophrenia, the method comprising administering to a subject a compound of formula (I), (II) or (III), a pharmaceutically acceptable salt thereof, or a composition thereof. **CHEMICAL FORMULA** (wherein X is a halogen) Here, the compound of formula (III) is also referred to herein as "JMF1907".

[0009] In another embodiment, the compound is N 6 -[(3-halothien-2-yl)methyl]adenosine, N 6 -[(4-halothien-2-yl)methyl]adenosine, and N 6 -[(5-halothien-2-yl)methyl]adenosine may be selected. Preferably, the compound is N 6 -[(5-bromothien-2-yl)methyl]adenosine (also referred to as "JMF3464"), N 6 -[(4-bromothien-2-yl)methyl]adenosine, N 6 -[(3-bromothien-2-yl)methyl]adenosine, N 6 -[(5-chlorothien-2-yl)methyl]adenosine (also referred to as "JMF3818"), N 6 -[(4-chlorothien-2-yl)methyl]adenosine, N 6 -[(3-chlorothien-2-yl)methyl]adenosine, or a combination thereof.

[0010] In another embodiment, the compound is N 6 -[(2-halothien-3-yl)methyl]adenosine, N 6 -[(4-halothien-3-yl)methyl]adenosine, and N 6 -[(5-halothien-3-yl)methyl]adenosine may be selected. Preferably, the compound is N 6 -[(2-bromothien-3-yl)methyl]adenosine, N 6 -[(4-bromothien-3-yl)methyl]adenosine, N 6 -[(5-bromothien-3-yl)methyl]adenosine, N 6 -[(2-chlorothien-3-yl)methyl]adenosine, N 6 -[(4-chlorothien-3-yl)methyl]adenosine, or N 6-[(5-chlorothien-3-yl)methyl]adenosine, or combinations thereof. In one embodiment, the compound, its pharmaceutically acceptable salt, or its composition is administered by oral, intravenous, intramuscular, subcutaneous or intraperitoneal routes.

Example

[0011] (Example 1) Evaluation of the effect of adenosine analog JMF3464 on schizophrenia Also referred to as "JMF3464", N6-[(5-bromothien-2-yl)methyl]adenosine having the following structure is a small adenosine analog. To determine the beneficial potential of JMF3464, the present invention used several behavioral tasks including METH-induced behavioral sensitization and conditioned place preference (CPP) to determine the effect of JMF3464 in vivo.

Chemical formula

[0012] Methods and Results Animals: Male mice (C57BL / 6; 2 - 3 months old) were purchased from National Taiwan University (Taipei, Taiwan) and maintained under standard conditions using a 12-hour light cycle / 12-hour dark cycle in its animal facility. All animal experimental procedures were performed in accordance with the guidelines established by the Institutional Animal Care and Use Committee (IACUC) of National Taiwan University and the Institute of Biomedical Sciences (IBMS) of Academia Sinica (Taipei, Taiwan). Spontaneous locomotor activity: Spontaneous locomotor activity was monitored and recorded for 1 hour using SMART 3.0 video tracking software (Panlab Harvard Apparatus, Barcelona, Spain) according to the manufacturer's protocol.

[0013] Effect of JMF3464 on spontaneous motor function Male drug-naïve WT mice (3 - 6 months old) received a single injection of JMF3464 (0.3, 0.5, 1, and 3 mg / kg, respectively) via intraperitoneal injection, and spontaneous motor activity was recorded immediately after injection. The vehicle group was used as the control group. The data were presented and analyzed as one-way ANOVA of the total distance traveled for 60 minutes (see Figure 1A) and two-way ANOVA of the distance for each 5-minute time bin (see Figure 1B). As shown in Figures 1A and 1B, injection of JMF3464 alone showed a dose-dependent effect on spontaneous motor activity, resulting in a slight decrease (about 20%) in the total spontaneous motor activity that occurred in all 5-minute time bins.

[0014] METH-induced behavioral sensitization Methamphetamine (METH) is a dopamine enhancer that increases synaptic dopamine in the brain and is frequently used to induce schizophrenia-like behaviors in mice. 6 . Therefore, the in vivo efficacy of JMF3464 was evaluated to determine its effect on the response induced by METH. As an experimental example, male METH-naïve WT mice (3 - 6 months old) received a co-injection of JMF3464 (0.3, 1, and 3 mg / kg, respectively) and METH (2 mg / kg) via intraperitoneal injection immediately after establishing 20 minutes of baseline spontaneous motor activity. Spontaneous motor activity was recorded for 60 minutes after injection. The saline + vehicle group and the METH + vehicle group were used as control groups. In addition, compound CGS21680, which is known to be useful for the treatment of schizophrenia, was used as a comparative example under the same experimental conditions as JMF3464. The obtained data were presented and analyzed as one-way ANOVA of the total distance traveled (see Figure 2) and two-way ANOVA of the distance for each 5-minute time bin (see Figures 3A and 3B). As shown in Figure 2, when various doses (0.3, 1, and 3 mg / kg) of JMF3464 were combined with METH (2 mg / kg), METH caused approximately 200% hyperlocomotion. Furthermore, co-treatment with JMF3464 dose-dependently suppressed METH-induced hyperlocomotor activity, as in the CGS21680 control. Referring further to Figures 3A and 3B, at 3 mg / kg, administration with JMF3464 significantly decreased METH-induced hyperlocomotor activity compared to the METH + vehicle group, and the results were similar to those of the CGS21680 control.

[0015] Conditioned place preference (CPP) The METH-induced conditioned place preference (CPP) assay was further performed to investigate the therapeutic effect of JMF3464 against METH-induced addiction. Male METH-insensitive WT mice (3 - 6 months old) were pretreated with vehicle, 1 mg / kg of JMF3464, or 3 mg / kg of JMF3464, 10 minutes before the METH-induced (2 mg / kg) CPP procedure. The METH-induced CPP procedure is shown as follows. The conditioned place preference (CPP) paradigm is a standard preclinical behavioral model used to study the rewarding and aversive effects of drugs. The paradigm typically uses a two-compartment apparatus where each compartment has different contextual features (e.g., wall color / pattern and floor texture). The CPP model consists of three stages: pre-conditioning (baseline), conditioning, and post-conditioning (i.e., CPP test). During baseline, on the day before the conditioning stage, mice were allowed free access to all compartments for 15 minutes. The conditioning session consisted of administering a vehicle (control) or an unscheduled (experimenter-administered) injection of METH, then placing the animal in a different context and confining it for 30 minutes. In addition, 10 minutes before each METH conditioning session, each mouse received either 1 (or 3) mg / kg of JMF3464 (i.p.) or vehicle. Control and METH conditioning sessions were conducted on the same day (separated by 4 - 6 hours). These pairings were conducted over 3 days. During the conditioning session, METH-context association was acquired. After conditioning, the time spent on the non-preferred side was considered an index of CPP. Finally, on the day after the conditioning session, the mice underwent a CPP test, were again allowed free access to all compartments for 15 minutes, and the time spent on the side paired with METH was measured, which provided a measure of CPP expression. Administration of JMF3464 did not affect the METH-induced rewarding effect under the present test conditions. As shown in Figures 4A and 4B, neither 1 mg / kg nor 3 mg / kg of JMF3464 exerted an inhibitory effect on METH-induced CPP. Based on the above experimental results, it can be seen that JMF3464 significantly suppressed METH-induced hyperactivity. Furthermore, no effect of JMF3464 was observed on METH-induced behavioral sensitization after repeated use, nor on METH-induced reward in CPP.

[0016] (Example 2) Evaluation of the Effect of Adenosine Analogue JMF1907 on Schizophrenia Similar to compound JMD3464, compound JMF1907 of formula (III) represented by the following structure is also a small adenosine analogue. To determine the beneficial potential of JMF1907, the present invention determined the effect of JMF1907 in vivo using METH-induced behavioral sensitization. [Chemical formula] JMF1907

[0017] Methods and Results Animals: Male mice (C57BL / 6; 2 - 3 months old) were purchased from National Taiwan University (Taipei, Taiwan) and maintained under standard conditions using a 12-hour light cycle / 12-hour dark cycle in its animal facility. All animal experimental procedures were conducted in accordance with the guidelines established by the IACUC of National Taiwan University and the IBMS of Academia Sinica (Taipei, Taiwan). Spontaneous locomotor activity: Spontaneous locomotor activity was monitored and recorded for 1 hour using SMART 3.0 video tracking software (Panlab Harvard Apparatus, Barcelona, Spain) according to the manufacturer's protocol.

[0018] METH-Induced Behavioral Sensitization for JMF1907 Similar to the above JMF3464 study, the in vivo efficacy of JMF1907 was evaluated to determine its effect on the response induced by METH. As an experimental example, male METH-naive WT mice (3 - 6 months old) received a simultaneous injection of JMF1907 (1 mg / kg) and METH (2 mg / kg) via intraperitoneal injection (i.p.) immediately after establishing a 20-minute baseline locomotor activity. Locomotor activity was recorded for 60 minutes after injection. In this study, the saline + vehicle (5% DMSO) group and the METH + vehicle (5% DMSO) group were used as control groups. In addition, the above compound JMF3464 and the compound S-(4-nitrobenzyl)-6-thioinosine (NBTI), which is known as an inhibitor of the equilibrative nucleoside transporter 1 (ENT1) transporter, were used as comparative examples under the same experimental conditions as JMF1907. The obtained data were represented and analyzed as one-way analysis of variance of the total movement distance (see Figure 5) and two-way analysis of variance of the distance for each 5-minute time bin (see Figure 6). As shown in Figure 5, with regard to overall locomotor activity, an injection of 2.0 mg / kg of METH effectively induced hyperlocomotor activity similar to schizophrenic-like behavior. At the same dosage, 1 mg / kg of JMF1907 significantly improved METH-induced hyperlocomotor behavior compared to the other two drugs JMF3464 and NBTI. That is, JMF1907 injection significantly improved the behavioral performance of the increase in spontaneous activity induced by METH. Furthermore, referring to Figure 6, when the test time was divided into 5-minute intervals, it can be observed that the mice in the five groups showed no significant difference at the baseline level of their spontaneous activity before drug administration. However, after drug administration, it was observed that METH significantly induced an increase in spontaneous activity. However, it can be seen that compared to the other two drugs JMF3464 and NBTI, JMF1907 showed a relative improvement in METH-induced hyperlocomotor behavior with an efficacy of improvement equivalent to that of the control group (saline + vehicle). That is, in the 60-minute open field experiment, JMF1907 (1 mg / kg, i.p.) injection showed greater efficacy in improving METH-induced hyperlocomotor behavior compared to the other drugs. As a result, it can be demonstrated that the claimed compounds of the invention, such as JMF3464 and JMF1907, can actually suppress the hyperlocomotor response induced by excessive dopamine, and thus have the potential to treat schizophrenia.

[0019] References JPEG2025520975000006.jpg137170

Claims

1. A composition for use in a method of treating schizophrenia, the method comprising administering to a subject in need thereof a composition comprising a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof. [[Chemical Formula 2]] (wherein X is halogen)

2. The compound is N 6 -[(3-halothien-2-yl)methyl]adenosine, N 6 -[(4-halothien-2-yl)methyl]adenosine, and N 6 -[(5-halothien-2-yl)methyl]adenosine, and the composition for use according to claim 1, selected from the group consisting of

3. The compound is N 6 -[(5-bromothien-2-yl)methyl]adenosine, N 6 -[(4-bromothien-2-yl)methyl]adenosine, N 6 -[(3-bromothien-2-yl)methyl]adenosine, N 6 -[(5-chlorothien-2-yl)methyl]adenosine, N 6 -[(4-chlorothien-2-yl)methyl]adenosine, and N 6 -[(3-chlorothien-2-yl)methyl]adenosine, and a composition for use according to claim 2, selected from the group consisting of

4. The compound is N 6 -[(2-halothien-3-yl)methyl]adenosine, N 6 -[(4-halothien-3-yl)methyl]adenosine, and N 6 -[(5-halothien-3-yl)methyl]adenosine, and a composition for use according to claim 1, selected from the group consisting of

5. The compound is N 6 -[(2-bromothien-3-yl)methyl]adenosine, N 6 -[(4-bromothien-3-yl)methyl]adenosine, N 6 -[(5-bromothien-3-yl)methyl]adenosine, N 6 -[(2-chlorothien-3-yl)methyl]adenosine, N 6 -[(4-chlorothien-3-yl)methyl]adenosine, and N 6 The composition for use according to claim 4, selected from the group consisting of -[(5-chlorothien-3-yl)methyl]adenosine.

6. The composition for use according to claim 1, which is administered by an oral, intravenous, intramuscular, subcutaneous or intraperitoneal route.

7. The composition for use according to claim 1, further comprising a pharmaceutically acceptable carrier, excipient or vehicle.

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