Voltage-gated potassium channel openers for use in the treatment of anhedonia

Abstract

The present disclosure is directed, inter alia, to a voltage-gated potassium channel opener, N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide (Compound A), for use in methods for treating anhedonia in a subject, e.g., a human. The present disclosure is further directed to various improved means of administration of Compound A.

Description

[Technical field]

[0001] The present disclosure is directed, inter alia, to a voltage-gated potassium channel opener, N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide (Compound A), for use in methods for treating anhedonia in a subject, e.g., a human. The present disclosure is further directed to various improved means of administration of Compound A. [Background technology]

[0002] Anhedonia, characterized by a decreased ability to experience pleasure and / or a decreased interest in participating in pleasurable activities, is a prominent symptom of many neuropsychiatric disorders. The severity of anhedonia may be quantified according to the 14-point Snaith-Hamilton Pleasure Scale (SHAPS). Snaith et al., Br. J. Psychiatry 1995;167:99-103; Nakonezny et al., Int. Clin. Psychopharmacol. 2010;25(6):328-333.

[0003] Anhedonia occurs frequently in depression, for example, major depressive disorder and stress-induced depression.Anhedonia is the core symptom of major depressive disorder, and is found in approximately 70% of people suffering from this condition.Individuals who experience anhedonia can be diagnosed with depression, even if they do not have other symptoms that reflect low or depressed mood.

[0004] Anhedonia is commonly listed as one component of the negative symptoms in schizophrenia. Although five domains are usually used to classify negative schizophrenia symptoms, factor analysis of the questionnaire yielded two factors, one including pleasure and motivation deficits. People with schizophrenia have retrospectively reported experiencing fewer positive emotions than healthy individuals.

[0005] Anhedonia is associated with substance use disorders and adversely affects treatment outcome. Anhedonia is common in people with dependence on a wide variety of drugs, including alcohol, opioids, and nicotine.

[0006] Anhedonia occurs frequently in Parkinson's disease, with reported rates ranging from 7% to 45%. Anhedonia also occurs in obsessive-compulsive disorders (e.g., binge eating syndrome).

[0007] Social anhedonia is defined as a lack of interest in social contacts and a lack of comfort (pleasure) in social situations and is characterized by social withdrawal (withdrawal), which is typically manifested as a disinterest in social interactions with other people.

[0008] Sexual anhedonia (sexual anhedonia) is most frequently found in men and is sometimes called "ejaculatory anhedonia." Men suffering from this condition ejaculate without any sensation of pleasure. Sexual anhedonia also occurs in women and manifests as a lack of pleasure associated with orgasm. Use of selective serotonin reuptake inhibitors (SSRIs) can cause sexual anhedonia.

[0009] Depression is a leading cause of disability worldwide. However, available treatments are only partially effective for many patients and have additional limitations, including slow onset of therapeutic action and undesirable side effects. Currently, treatments for depression approved by the US Food and Drug Administration (FDA) consist mostly of serotonergic and noradrenergic agents, which share the same basic pharmacology and mechanisms of action, largely based on discoveries made decades ago. This lack of mechanistic diversity leaves little opportunity for improved patient outcomes or individualized treatment approaches.

[0010] Given the occurrence of anhedonia, including the various diseases and conditions mentioned above, there is a need for a corresponding anhedonia treatment. [Prior art documents] [Non-patent literature]

[0011] [Non-Patent Document 1] Snaith et al. Br.J.Psychiatry 1995;167:99-103 [Non-Patent Document 2] Nakonezny et al., Int. Clin. Psychopharmacol. 2010;25(6):328-333 Summary of the Invention [Means for solving the problem]

[0012] This disclosure describes certain methods and uses of the small molecule N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide (herein referred to as "Compound A").

[0013] In one embodiment, the disclosure is directed to a method of treating anhedonia in a subject (preferably a mammal such as a human) in need thereof, comprising administering (e.g., orally) to the subject a therapeutically effective amount of Compound A. In some embodiments, the disclosure is directed to the use of Compound A in treating anhedonia in a subject (preferably a mammal such as a human) in need thereof. In some embodiments, the anhedonia subject suffers from sexual anhedonia or social anhedonia. In some examples, the above-mentioned method or use comprises reversing hyperactivity in the ventral tegmental area (VTA) of a subject with anhedonia.

[0014] In one embodiment, anhedonia prior to treatment with Compound A has a severity, as measured by the SHAPS, of at least 4. In other embodiments, anhedonia prior to treatment with Compound A has a severity, as measured by the SHAPS, of at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, or 14.

[0015] In certain examples, the anhedonia treated by administration of Compound A is a symptom of a neuropsychiatric disorder, such as a depressive disorder, a substance-related disorder, a psychotic disorder, a personality disorder, an epileptic disorder, or a combination thereof. In one embodiment, the depressive disorder is major depressive disorder (MDD). In some embodiments, the depressive disorder is post-traumatic stress disorder (PTSD), severe mood dysregulation disorder, persistent depressive disorder, bipolar spectrum disorder, bipolar depression, postpartum depression, premenstrual dysphoric disorder (PMDD), seasonal affective disorder (SAD), atypical depression, treatment-resistant depression (TRD), depression associated with agitation or anxiety, adjustment disorder with depressed mood, prolonged depressive reaction, or a combination thereof. In some embodiments, the substance-related disorder comprises a dependency on one or more drugs, including alcohol, cocaine, opioids, nicotine, or a combination thereof. In some embodiments, the neuropsychiatric disorder is schizophrenia, schizoaffective disorder, or schizotypal disorder. In some embodiments, the neuropsychiatric disorder is an obsessive-compulsive disorder, such as binge eating syndrome. In some embodiments, the neuropsychiatric disorder is an extrapyramidal disorder, Alzheimer's disease, dementia, Parkinson's disease, PTSD, anorexia nervosa, panic disorder, attention deficit hyperactivity disorder (ADHD), chronic migraine with or without aura, migraine aura without headache, chronic tension headache, persistent hemicrania, chronic headache including new onset persistent daily headache, dementia, multiple sclerosis, or dysthymic disorder. In some embodiments, the epileptic disorder is epilepsy, focal onset epilepsy, or post-stroke epilepsy. In some embodiments, the anhedonia treated by administration of Compound A is associated with cancer, chronic pain, HIV / AIDs, lupus, or hypothyroidism.

[0016] In a further embodiment, the method of treating anhedonia comprising administering a therapeutically effective amount of Compound A, or the use of Compound A in treating anhedonia, further comprises enhancing the opening of Kv7 potassium channels in a subject (e.g., a human).

[0017] In another embodiment, the present disclosure is directed to a method of opening or enhancing the opening of Kv7 potassium channels in a subject (preferably a mammal such as a human), comprising administering to the subject an effective amount of compound A, or the use of compound A in opening or enhancing the opening of Kv7 potassium channels in a subject, wherein the subject suffers from anhedonia, such as various types of anhedonia, including anhedonia associated with major depressive disorder (MDD), post-traumatic stress disorder (PTSD), schizophrenia, substance-related disorder, Parkinson's disease, depression associated with agitation or anxiety, epilepsy, or obsessive-compulsive disorder (e.g., binge eating syndrome), and disorders having symptoms of anhedonia as described herein.

[0018] In some embodiments, the Kv7 potassium channel is one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.5. In certain examples, the opening or enhanced opening of one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.5 potassium channels is selective over Kv7.1. In other examples, the method includes the opening or enhanced opening of Kv7.2 / Kv7.3 (KCNQ2 / 3) potassium channels.

[0019] In certain examples, administering Compound A to the subject comprises administering a dose of Compound A between 2 and 200 mg per administration. In other examples, administering to the subject comprises a dose of 5 to 1000 mg administered daily, every other day, or weekly. In further examples, administering to the subject comprises a dose of 0.05 to 20 mg / kg, e.g., 0.1 to 5 mg / kg, administered daily, every other day, or weekly.

[0020] In some embodiments of the methods and uses, Compound A is orally administered to a subject (preferably a mammal, such as a human) between about 30 minutes before and about 2 hours after ingestion of a meal, for example, Compound A may be orally administered to a subject during or within 15 minutes of ingestion of a meal. Alternatively, Compound A may be orally administered to a subject regardless of the timing of a previous or subsequent meal.

[0021] Compound A is a small molecule currently being developed for the treatment of seizure disorders and its use as a potassium channel modulator is disclosed in U.S. Pat. Nos. 8,293,911 and 8,993,593, and U.S. patent application Ser. Nos. 16 / 409,684 and 16 / 410,851, the disclosures of which are incorporated herein by reference in their entireties.

[0022] These and other aspects of the present disclosure will become apparent upon reference to the following detailed description, and to this end, various references are set forth herein which describe in more detail certain background information and procedures, each of which is incorporated herein by reference in its entirety. [Brief description of the drawings]

[0023] [Figure 1] Figure 1 shows the effect of Compound A (1, 3 and 8 mg / kg, orally) in the progressive ratio test (PRT) for all rats (N=32). Statistical significance ("asterisk") was observed at the 3 and 8 mg / kg doses in both lever pressing (top graph) and breaking point (bottom graph) measurements (p<0.05 vs. vehicle). [Diagram 2] Figure 2 shows the effect of Compound A (1, 3 and 8 mg / kg, orally) in the progressive ratio test (PRT) for "high" vs. "low" responding rat subgroups (N=11 / subgroup). In both lever pressing (top graph) and breaking point (bottom graph) measures, statistical significance ("asterisk") was observed at the 3 and 8 mg / kg doses in the "low" responding rat subgroup (p<0.05 vs. vehicle) using a two-way mixed factorial ANOVA. [Diagram 3]Figure 3 shows the effect of Compound A (1, 3 and 8 mg / kg, orally) in the progressive ratio test (PRT) for the "low" responding rat subgroup (N=11 / subgroup). Using a two-way ANOVA for the low responding rat subgroup, statistical significance ("asterisk") was observed for the 3 and 8 mg / kg doses in the lever pressing (top graph) measure, and statistical significance ("asterisk") was observed for the 3 mg / kg dose in the breaking point (bottom graph) measure (p<0.05 vs. vehicle). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] In particular, the present disclosure relates to new and improved methods and uses of Compound A for the treatment of anhedonia by administering Compound A orally or by other routes to a subject in need thereof, preferably a mammal such as a human.

[0025] In the following disclosure, certain specific details are given to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the methods and uses described herein may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless otherwise stated, throughout this specification and the appended claims, the word "comprise" and its derivatives, such as "comprises" and "comprising," should be construed in an open-ended, inclusive sense, i.e., "including, but not limited to." Moreover, the subheadings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0026] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in one embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Moreover, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly contradicts otherwise. It should also be noted that the terms "or" and "or" are generally used in the sense of including "and / or" unless the context clearly contradicts otherwise.

[0027] 1. Definition As used in this specification and the appended claims, unless specifically stated to the contrary, the following terms and abbreviations have the meanings indicated.

[0028] "Anhedonia" as used herein refers to a marked decrease in interest or pleasure in all or almost all activities. Mild anhedonia is sometimes called hypohedonia.

[0029] "Compound A" refers to a compound having the formula below and the compound name N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide. [ka] The preparation of compound A and its use as a Kv7.2 / Kv7.3 (KCNQ2 / 3) opener are disclosed in US Patent No. 8,293,911 and US Patent No. 8,993,593, and US Patent Application No. 16 / 409,684 and US Patent Application No. 16 / 410,851. Compound A enhances or increases the opening of voltage-gated potassium channels Kv7.2 and Kv7.3 (Kv7.2 / Kv7.3), and the enhancement or increase in the opening of voltage-gated potassium channels Kv7.2 and Kv7.3 (Kv7.2 / Kv7.3) is important in controlling the excitability of neuronal cells. Compound A is used in the methods and uses described herein.

[0030] "Social anhedonia" as used herein refers to a lack of interest in social contact and lack of comfort in social situations. Social anhedonia is characterized by social withdrawal and typically manifests as a lack of interest in social interactions with other people. This trait is considered to be a central feature and predictor of schizophrenia spectrum disorders.

[0031] As used herein, a "therapeutically effective amount" refers to an amount of Compound A sufficient to treat a described disease, disorder, or condition in a human subject, or to obtain a desired described effect on the disease, disorder, or condition, or one or more mechanisms underlying the disease, disorder, or condition. In certain embodiments, when Compound A is administered to treat anhedonia, a therapeutically effective amount refers to an amount of Compound A that, upon administration to a human, treats or ameliorates anhedonia in the human, or produces a detectable therapeutic effect in the human suffering from anhedonia. This effect can be detected, for example, by a reduction in the number of anhedonia symptoms (e.g., "liking" or "wanting") or a reduction in the severity of anhedonia.

[0032] "Treatment" as used herein refers to therapeutic applications involving the administration of Compound A to improve the indicated disease, disorder or condition or one or more underlying mechanisms of the disease, disorder or condition in a human subject, including slowing or stopping the progression of one or more of the indicated diseases, disorders or conditions or underlying mechanisms. In certain embodiments, when Compound A is administered for the treatment of anhedonia, treatment refers to therapeutic applications to slow or stop the progression of anhedonia (i.e., slow or stop the increase in the intensity or frequency of anhedonia) and / or reverse anhedonia. Reversal of anhedonia differs from therapeutic applications that slow or stop anhedonia in that the reversal method not only stops the progression of anhedonia, but also moves some cellular behavior toward the normal state that would be observed in the absence of anhedonia. In some embodiments, treatment of anhedonia involving administration of Compound A is accompanied by an alteration in the cellular activity of one or more Kv7 potassium channels (e.g., Kv7.2, Kv7.3, Kv7.4, and / or Kv7.5, particularly Kv7.2 and / or Kv7.3, optionally in preference to Kv7.1) to normal levels that would be observed in the absence of anhedonia.

[0033] "Fed conditions" refers to a state in which food has been consumed during the period from about 4 hours before the oral administration of Compound A to about 4 hours after the administration of Compound A. The food may be solid, liquid, or a mixture of solid and liquid foods, provided that the food has sufficient bulk and fat content to not be rapidly dissolved and absorbed in the stomach. In some examples, the food is a meal such as breakfast, lunch, dinner, or baby food (e.g., formula or breast milk). Compound A may be orally administered to a subject, for example, between about 30 minutes before and about 2 hours after the ingestion of a meal, and most preferably, Compound A is orally administered during or within 15 minutes after the ingestion of a meal.

[0034] "Under fasted conditions" refers to the absence of food intake for a period beginning at least 4 hours prior to oral administration of Compound A and ending approximately 4 hours after administration of Compound A.

[0035] 2. Embodiment Provided herein are methods and uses of a Kv7 activator known as Compound A (N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide) as a treatment for anhedonia. In certain examples, the methods and uses act by reversing hyperactivity in the ventral tegmental area (VTA), for example, through enhancement of Kv7-mediated M-current. Anhedonia includes those listed for disorders disclosed herein, for example, anhedonia associated with depression (e.g., major depressive disorder) and social anhedonia.

[0036] This disclosure describes the study of established models of stress-induced depression and anhedonia.For example, animals vulnerable to CSDS (chronic social defeat stress) can be studied in the forced swimming test for social avoidance (resident / intruder paradigm) and for the antidepressant activity of Compound A.Such vulnerable animals can also be studied for sugar preference for the effect of treating anhedonia.

[0037] In clinical trials, anhedonia assessments can be performed in humans using the Snaith-Hamilton Pleasure Scale (SHAPS), Temporal Experience of Pleasure Scale (TEPS), Effort Expenditure for Rewards Task (EEfTR), Fawcett-Clark Pleasure Capacity Scale-Physical Pleasure (FCPCS), or the Physical Anhedonia Scale of Chapman (PAS), for example to compare the effects of Compound A to a placebo.

[0038] In some embodiments, the present disclosure is directed to a method of treating anhedonia in a subject (preferably a mammal, such as a human) in need thereof, comprising administering (e.g., orally) to the subject a therapeutically effective amount of Compound A. Similarly, in certain embodiments, the present disclosure is directed to the use of Compound A in treating anhedonia in a subject (preferably a mammal, such as a human) in need thereof.

[0039] In some examples, the anhedonic subject treated by administration of Compound A suffers from sexual anhedonia or social anhedonia. In other examples, the anhedonic subject treated by administration of Compound A does not suffer from sexual anhedonia or social anhedonia. In certain examples, the anhedonia treated by administration of Compound A is a symptom of a neuropsychiatric disorder, such as a depressive disorder, a substance-related disorder, a psychotic disorder, a personality disorder, an epileptic disorder, or a combination thereof.

[0040] In certain embodiments, the neuropsychiatric disorder is a depressive disorder.In some such embodiments, the depressive disorder is stress-induced depression, major depressive disorder (MDD), post-traumatic stress disorder (PTSD), severe mood dysregulation disorder, persistent depressive disorder, bipolar spectrum disorder, bipolar depression, postpartum depression, premenstrual dysphoric disorder (PMDD), seasonal affective disorder (SAD), atypical depression, treatment-resistant depression (TRD), depression associated with agitation or anxiety, adjustment disorder with depressed mood, prolonged depressive reaction, or combinations thereof.In certain embodiments, the depressive disorder is MDD.

[0041] In other embodiments, the neuropsychiatric disorder is a substance-related disorder, hi some embodiments, the substance-related disorder comprises an addiction to one or more drugs, including alcohol, cocaine, opioids, nicotine, or combinations thereof.

[0042] In some embodiments, the neuropsychiatric disorder is schizophrenia, schizoaffective disorder, schizotypal disorder, extrapyramidal disorder, Alzheimer's disease, dementia, Parkinson's disease, obsessive-compulsive disorder, PTSD, anorexia nervosa, panic disorder, attention-deficit hyperactivity disorder (ADHD), chronic headache including chronic migraine with or without aura, migraine aura without headache, chronic tension headache, hemicrania continua, new-onset daily persistent headache, dementia, multiple sclerosis, or dysthymic disorder.

[0043] In some embodiments, the epileptic disorder is epilepsy, focal onset epilepsy, or post-stroke epilepsy.

[0044] In some embodiments, the anhedonia treated by administration of Compound A is associated with cancer, chronic pain, HIV / AIDs, lupus, or hypothyroidism.

[0045] In some embodiments, the method of treating anhedonia by administering a therapeutically effective amount of Compound A, or the use of Compound A in treating anhedonia, comprises enhancing the opening of Kv7 potassium channels in a subject (preferably a mammal, such as a human).

[0046] In certain examples, the methods and uses described herein selectively open or selectively enhance the opening of Kv7 potassium channels, such as one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.5 over Kv7.1. In some embodiments, the methods or uses are selective for Kv7.2 over Kv7.1. In other embodiments, the methods or uses are selective for Kv7.3 over Kv7.1. In still other embodiments, the methods or uses are selective for Kv7.4 over Kv7.1. In still further other embodiments, the methods or uses are selective for Kv7.5 over Kv7.1. In certain embodiments, the methods or uses are selective for Kv7.2 and Kv7.3 over Kv7.1. In certain embodiments, the methods or uses are selective for Kv7.2 and Kv7.3 over other Kv7 potassium channels. In certain embodiments, the method or use is selective for Kv7.2 and Kv7.3 over Kv7.4 and Kv7.5.

[0047] In certain embodiments, the present disclosure provides a method of reversing hyperactivity in the ventral tegmental area (VTA) in a subject in need thereof (preferably a mammal, such as a human, suffering from anhedonia), comprising administering to the subject (e.g., orally) an effective amount of Compound A. Similarly, in some embodiments, the present disclosure is directed to the use of Compound A in reversing hyperactivity in the VTA in a subject in need thereof (preferably a mammal, such as a human, suffering from anhedonia).

[0048] In certain examples, the methods or uses described herein selectively open or selectively enhance the opening of Kv7 potassium channels, such as one or more of Kv7.2, Kv7.3, Kv7.4, and Kv7.5 over Kv7.1. In some embodiments, the methods or uses are selective for Kv7.2 over Kv7.1. In other embodiments, the methods or uses are selective for Kv7.3 over Kv7.1. In still other embodiments, the methods or uses are selective for Kv7.4 over Kv7.1. In still further other embodiments, the methods or uses are selective for Kv7.5 over Kv7.1. In certain embodiments, the methods or uses are selective for Kv7.2 and Kv7.3 over Kv7.1. In certain embodiments, the methods or uses are selective for Kv7.2 and Kv7.3 over other Kv7 potassium channels. In certain embodiments, the method or use is selective for Kv7.2 and Kv7.3 over Kv7.4 and Kv7.5.

[0049] In some embodiments, the treatment of anhedonia is achieved by administering Compound A to the patient. Such administration may be, for example, by oral, inhalation, sublingual, buccal, ocular, auricular, vaginal, rectal, dermal, topical, or transdermal administration; by intravenous, intramuscular, intrathecal, or subcutaneous injection; or by implantation. In certain embodiments, administration is oral administration.

[0050] As an alternative to oral administration, in certain instances, other administration routes of compound A, such as parenteral administration, may be used in the methods and uses described herein. Parenteral administration routes include subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques, or implantation, or inhalation. For example, compound A can be administered by injection, such as intravenous, intramuscular, intrathecal, or subcutaneous injection. In certain embodiments, the doses of compound A discussed herein are intended for oral administration and can be converted to doses suitable for parenteral administration, including administration by injection, for example by reducing the oral dose by about half.

[0051] Other suitable routes of administration for administration of Compound A according to the methods and uses described herein include sublingual and buccal (e.g., using a film or other composition that dissolves in the buccal cavity under the tongue or inside the cheek), ocular (e.g., eye drops), otic (e.g., by ear drops), oral or nasal inhalation (e.g., by insufflation or spray), dermal or topical (external) (e.g., by cream or lotion), or transdermal (e.g., by skin patch). In addition to oral administration, other enteral routes of administration can be used for Compound A, including vaginal and rectal (e.g., by ointments, suppositories, enemas).

[0052] In one embodiment, the methods and uses described herein, e.g., methods of treating or uses in treating anhedonia in a subject in need thereof (preferably a mammal such as a human), are effected by administering (e.g., orally) a therapeutically effective amount of Compound A, e.g., about 0.05 mg / kg to about 20 mg / kg, e.g., about 0.05 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.05 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.05 mg / kg to about 2 mg / kg, or about 0.1 mg / kg to about 2 mg / kg. More specific representative amounts include 0.05mg / kg, 0.1mg / kg, 0.2mg / kg, 0.3mg / kg, 0.4mg / kg, 0.5mg / kg, 0.6mg / kg, 0.7mg / kg, 0.8mg / kg, 0.9mg / kg, 1mg / kg, 1.1mg / kg, 1.2mg / kg, 1.3mg / kg, 1.4mg / kg, 1.5mg / kg, 1.6mg / kg, 1.7mg / kg, 1.8mg / kg, 1.9mg / kg, 2mg / kg, 5mg / kg, 8mg / kg, 10mg / kg, 12mg / kg, 15mg / kg, 18mg / kg, or 20mg / kg, or any range of amounts created by using two of the above amounts as endpoints. In some embodiments, the method or use comprises administering (e.g., orally) 0.1-5mg / kg of compound A. In certain embodiments, the method comprises administering (e.g., orally) 0.2-0.5 mg / kg of Compound A. In some embodiments, the method or use comprises administering (e.g., orally) 0.05-20 mg / kg of Compound A. In certain embodiments, the method comprises administering (e.g., orally) 1-10 mg / kg of Compound A.

[0053] In certain examples, the disclosure provides a method of treating anhedonia in a subject (preferably a mammal such as a human) in need thereof, comprising administering (e.g., orally) to the subject a therapeutically effective amount of Compound A, wherein the anhedonia includes various types of anhedonia and disorders having symptoms of anhedonia as described herein, including stress-induced depression, major depressive disorder (MDD), post-traumatic stress disorder (PTSD), schizophrenia, substance-related disorders, Parkinson's disease, epilepsy, sexual anhedonia, and social anhedonia, wherein Compound A is administered to the human at a dose of 0.05-5 mg / kg, such as 0.1-5 mg / kg, 0.05-2 mg / kg, or 0.1-2 mg / kg. In some embodiments, the method comprises administering the compound to the subject in an amount of about 0.05 mg / kg, 0.1 mg / kg, 0.15 mg / kg, 0.2 mg / kg, 0.24 mg / kg, 0.25 mg / kg, 0.3 mg / kg, 0.35 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.75 mg / kg, 0.8 mg / kg, 0.81 mg / kg, 0.85 mg / kg, 0.9 mg / kg, 1 mg / kg, 1.2 mg / kg, 1.5 mg / kg, 1.8 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, or 5 mg / kg, or any range created by using two of the recited amounts as endpoints.

[0054] In some examples, the disclosure provides a method of treating anhedonia in a subject (e.g., a human) in need thereof, comprising administering (e.g., orally) to the subject a therapeutically effective amount of Compound A, wherein the anhedonia includes various types of anhedonia and disorders having symptoms of anhedonia as described herein, including stress-induced depression, major depressive disorder (MDD), post-traumatic stress disorder (PTSD), schizophrenia, substance-related disorders, Parkinson's disease, sexual anhedonia, and social anhedonia, wherein Compound A is administered to the human at a dose of 0.5-10 mg / kg, e.g., 0.5-8 mg / kg. , 1-10 mg / kg, or 1-8 mg / kg, for example about 0.5 mg / kg, 0.8 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 2.6 mg / kg, 2.8 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.2 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg, or any range created by using two of the recited amounts as endpoints.

[0055] In some embodiments, the methods and uses described herein, e.g., methods or uses in treating anhedonia in a subject (e.g., a human) in need thereof, are accomplished by administering (e.g., orally) a therapeutically effective amount of Compound A, e.g., 2-200 mg of Compound A, in a single or multiple dosage units. For example, the methods may be administered in a single or multiple dosage units of about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 6mg, about 37mg, about 38mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 61mg, about 62mg, about 63mg, about 64mg, about 65mg, about 66mg, about 67mg, about 68mg, about 69mg, about 70mg, about 71mg, about 7 2mg, about 73mg, about 74mg, about 75mg, about 76mg, about 77mg, about 78mg, about 79mg, about 80mg, about 81mg, about 82mg, about 83mg, about 84mg, about 85mg, about 86mg, about 87mg, about 88mg, about 89mg, about 90mg, about 91mg, about 92mg, about 93mg, about 94mg, about 95mg, about 96mg, about 97mg, about 98mg, about 99mg, about 100mg, about 101mg, about 102mg, about 103mg, about 104mg, about 105mg, about 106mg, about 107mg, about 108mg, about 109mg, about 110mg, about 111mg, about 112mg, about 113mg, about 114mg, about 115mg, about 116mg, about 117mg, about 118mg, about 119mg, about 120mg, about 121mg, about 122mg, about 123mg, about 124mg, about 125mg, about 126mg, about 127mg, about 129mg, about 130mg, about 131mg, about 132mg, about 133mg, about 134mg, about 135mg, about 136mg, about 137mg, about 138mg,about 139 mg, about 140 mg, about 141 mg, about 142 mg, about 143 mg, about 144 mg, about 145 mg, about 146 mg, about 147 mg, about 148 mg, about 149 mg, about 150 mg, about 151 mg, about 152 mg, about 153 mg, about 154 mg, about 155 mg, about 156 mg, about 157 mg, about 158 ​​mg, about 159 mg, about 160 mg, about 161 mg, about 162 mg, about 163 mg, about 164 mg, about 165 mg, about 166 mg, about 167 mg, about 168 mg, about 169 mg, about 170 mg, about 171 mg, about 172 mg, about 173 mg, about 174 mg, about 175 mg, about The method or use may include administering (e.g., orally) 176 mg, about 177 mg, about 178 mg, about 179 mg, about 180 mg, about 181 mg, about 182 mg, about 183 mg, about 184 mg, about 185 mg, about 186 mg, about 187 mg, about 188 mg, about 189 mg, about 190 mg, about 191 mg, about 192 mg, about 193 mg, about 194 mg, about 195 mg, about 196 mg, about 197 mg, about 198 mg, about 199 mg, or about 200 mg, or any range of amounts created by using two of the above amounts as endpoints. In some embodiments, the method or use includes oral administration of 5 to 100 mg of Compound A to a subject (e.g., a human) in a single or multiple dosage unit. In some embodiments, the method or use comprises oral administration to a subject (e.g., a human) of 5 to 80 mg of Compound A in a single or multiple dose unit. In some embodiments, the method or use comprises oral administration to a subject (e.g., a human) of 5 to 40 mg of Compound A in a single or multiple dose unit.

[0056] In some aspects, the methods and uses described herein, such as the methods or uses for treating anhedonia in a subject (e.g., a human) in need thereof, are achieved by administering (e.g., orally) at least 5 mg of Compound A, such as at least 5, 10, 15, 20, 25, 30, 35, 50, 75, or 100 mg of Compound A. In some embodiments, the methods and uses described herein, such as the methods or uses for treating anhedonia in a subject (e.g., a human) in need thereof, are achieved by administering (e.g., orally) at least 20 mg of Compound A per day, such as at least 30, 40, 60, 75, 85, 100, 125, 150, 175, or 200 mg of Compound A per day to the subject (e.g., a human). In some embodiments, the methods and uses described herein, e.g., methods or uses in treating anhedonia in a subject in need thereof, are achieved by administering (e.g., orally) to a subject (e.g., a human) at least 5 mg of Compound A 1, 2, 3, 4, or 5 days per week, e.g., at least 20, 40, 60, 75, 85, 100, 125, 150, 175, or 200 mg of Compound A 1, 2, 3, 4, or 5 days per week. In some embodiments, Compound A is administered every other day, every third day, or twice a week.

[0057] In some embodiments, the methods and uses described herein, e.g., methods of treating or uses in treating anhedonia in a subject (e.g., a human) in need thereof, are achieved by administering (e.g., orally) a therapeutically effective amount of Compound A per day, e.g., 5-1000 mg per day or per week, e.g., 5-500 mg or 5-250 mg per day or per week. For example, the method or use may comprise administering to the patient about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215 mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, About 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg, about 36 0mg, about 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400mg, about 405mg, about 410mg, about 415mg, about 420mg, about 425mg, about 430mg , about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg, or about 1000 mg of Compound A per day (e.g., orally), or a range created by using two of the above amounts as endpoints.In some embodiments, the method or use comprises orally administering to a subject (e.g., a human) 5-200 mg of Compound A per day, e.g., 10, 15, 20, 25, 30, 35, or 40 mg per day to 75, 100, 125, 150, 175, or 200 mg of Compound A per day, e.g., 5-150 mg per day. In some embodiments, the oral administration comprises 10, 20, 30, 40, 50, 75, 100, or 125 mg of Compound A per day, e.g., 100 mg per day, to a subject (e.g., a human).

[0058] In certain examples, the daily dose of Compound A is administered (e.g., orally) as multiple doses per day, such as 2, 3, 4, or 5 doses per day. For example, a daily dose of 100 mg may be administered as five doses of 20 mg, four doses of 25 mg, three doses of 33.3 mg, or two doses of 50 mg throughout the day.

[0059] In some embodiments, the above daily doses of Compound A are administered (e.g., orally) as a single dose. For example, about 5, 10, 15, 20, 25, or 30 mg to about 50, 65, 75, 100, 125, or 150 mg of Compound A per day can be administered orally as a single dose, including 10-30 mg, 20-50 mg, and 30-80 mg per day as a single dose, e.g., 25-30 mg per day as a single dose. Relatedly, any of the doses of Compound A discussed in the previous paragraphs may be included in a single unit dosage form or multiple unit dosage forms, e.g., two, three, or four unit dosage forms.

[0060] In certain embodiments, the methods and uses described herein achieve a steady state of Compound A within 6 to 9 days, for example within about 1 week, when using the daily dosing regimens disclosed herein.

[0061] In some embodiments, the methods and uses described herein for treating anhedonia by administering (e.g., orally) Compound A include administering according to a 12-hour (i.e., twice a day), 24-hour (i.e., once a day), 48-hour (i.e., once every two days), 72-hour, 96-hour, 5-day, 6-day, 1-week, or 2-week dosing regimen, in particular a 12-hour, 24-hour, or 48-hour dosing regimen. Such a regimen may include administering any of the doses or daily doses described above. For example, the present disclosure provides a method of treating anhedonia in a subject (e.g., a human) in need thereof, comprising administering (e.g., orally) to the subject a therapeutically effective amount of Compound A according to a 12-hour, 24-hour, 48-hour, 72-hour, 96-hour, 5-day, 6-day, 1-week, or 2-week interval, in particular a 12-hour, 24-hour, or 48-hour interval, wherein the amount of Compound A corresponds to any of the doses or daily doses described above. In certain such embodiments, Compound A is orally administered to a human subject under fed conditions, e.g., between about 30 minutes prior to ingestion of a meal and about 2 hours after ingestion of a meal, e.g., during or within 15 minutes after ingestion of a meal.

[0062] In further embodiments, the above-mentioned method or use of treating anhedonia by administering a therapeutically effective amount of Compound A comprises orally administering Compound A to a human subject under fed conditions, e.g., between about 30 minutes prior to ingestion of a meal and about 2 hours after ingestion of a meal, e.g., during a meal or within 15 minutes after ingestion of a meal. In some embodiments, oral administration of Compound A to a human subject under fed conditions significantly enhances the bioavailability and exposure of Compound A compared to oral administration of Compound A to a human subject under fasting conditions. In some embodiments, oral administration of Compound A to a human under fed conditions enhances one or more pharmacokinetic parameters of Compound A (e.g., C) compared to when the same amount of Compound A is orally administered to a subject under fasting conditions. max , AUC inf , T max , t 1 / 2λz etc.) to increase.

[0063] In certain embodiments, the methods and uses described herein administer compound A in the form of a pharma- ceutically acceptable oral composition comprising compound A and one or more pharma- ceutically acceptable carriers or excipients. The amount of compound A contained in these compositions may correspond to one or more of the amounts described herein. In some embodiments, the composition is a unit dose.

[0064] Examples of pharma- ceutically acceptable oral compositions comprising Compound A include solid formulations (such as tablets, capsules, lozenges, dragees, granules, powders, sprinkles, wafers, multiparticulates, and films), liquid formulations (such as aqueous solutions, elixirs, tonics, tinctures, slurries, suspensions, and dispersions), and aerosolized formulations (such as mists and sprays). In one embodiment, the pharma-ceutically acceptable oral composition of Compound A comprises a pediatric suspension or granules. All of the above amounts of Compound A may be included in such formulations, including, for example, capsules containing 5, 10, 15, 10, 25, 30, or 35 mg of Compound A.

[0065] Examples of compositions suitable for parenteral administration of compound A include sterile injectable solutions, suspensions, or dispersions, including aqueous or oily preparations, especially aqueous preparations. In some embodiments, compound A is administered according to the methods or uses described herein in sterile aqueous formulations for injection, including parenterally acceptable diluents or solvents, such as water, Ringer's solution, isotonic sodium chloride solution, buffered aqueous solutions, and aqueous solutions containing miscible alcohols, such as 1,3-butanediol. Further suitable excipients for parenteral formulations of compound A include mono- or diglycerides; fatty acids, such as oleic acid and its glyceride derivatives; natural pharma-ceutically acceptable oils, such as olive oil or castor oil (including their polyoxyethylated versions); long-chain alcohol diluents or dispersants, such as alkylcelluloses, including carboxymethylcellulose; and surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers.

[0066] In another embodiment, a kit is provided for the oral administration of Compound A for the treatment of anhedonia. Such a kit comprises a plurality of oral unit dosage forms of Compound A in combination with instructions for orally administering Compound A.

[0067] Further embodiments and examples of the present disclosure are described herein. These embodiments and examples are illustrative and should not be construed as limiting the scope of the claimed invention.

[0068] 3. Numbered Embodiments

[0069] Embodiment 1. A method of treating anhedonia in a human in need thereof, comprising administering to said human a therapeutically effective amount of Compound A, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide.

[0070] Embodiment 2. A method of reversing hyperactivity in the ventral tegmental area (VTA) in a human in need thereof, comprising administering to said human an effective amount of Compound A, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and said human suffering from anhedonia.

[0071] Embodiment 3. The method of embodiment 1 or embodiment 2, wherein said method comprises enhancing opening of Kv7 potassium channels in said human.

[0072] Embodiment 4. A method of enhancing the opening of Kv7 potassium channels in a human, comprising administering to said human an effective amount of Compound A, wherein Compound A is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, and said human suffering from anhedonia.

[0073] Embodiment 5. The method of embodiment 3 or embodiment 4, wherein said Kv7 potassium channel is one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.5.

[0074] Embodiment 6. The method of embodiment 5, wherein said method is selective for enhancing opening of one or more of Kv7.2, Kv7.3, Kv7.4, or Kv7.5 over Kv7.1.

[0075] Embodiment 7. The method of embodiment 3 or embodiment 4, wherein said method comprises opening of Kv7.2 / Kv7.3 (KCNQ2 / 3) potassium channels.

[0076] Embodiment 8. The method of any one of embodiments 1 to 7, wherein said anhedonia comprises sexual anhedonia.

[0077] Embodiment 9. The method of any one of embodiments 1 to 7, wherein said anhedonia comprises social anhedonia.

[0078] Embodiment 10. The method of any one of embodiments 1 to 7, wherein said anhedonia is a symptom of a neuropsychiatric disorder.

[0079] Embodiment 11. The method of embodiment 10, wherein said neuropsychiatric disorder is a depressive disorder, a substance-related disorder, a psychotic disorder, a personality disorder, an epileptic disorder, or a combination thereof.

[0080] Embodiment 12. The method of embodiment 11, wherein said neuropsychiatric disorder is a depressive disorder.

[0081] Embodiment 13. The method of embodiment 12, wherein said depressive disorder is stress-induced depression, major depressive disorder (MDD), post-traumatic stress disorder (PTSD), severe mood dysregulation disorder, persistent depressive disorder, bipolar spectrum disorder, bipolar depression, postpartum depression, premenstrual dysphoric disorder (PMDD), seasonal affective disorder (SAD), atypical depression, treatment-resistant depression (TRD), depression associated with agitation or anxiety, adjustment disorder with depressed mood, prolonged depressive response, or a combination thereof.

[0082] Embodiment 14. The method of embodiment 12, wherein said depressive disorder is MDD.

[0083] Embodiment 15. The method of embodiment 11, wherein said neuropsychiatric disorder is a substance-related disorder.

[0084] Embodiment 16. The method of embodiment 15, wherein the substance-related disorder comprises an addiction to alcohol, cocaine, opioids, or nicotine.

[0085] Embodiment 17. The method of embodiment 10, wherein the neuropsychiatric disorder is schizophrenia, extrapyramidal disorder, Alzheimer's disease, dementia, Parkinson's disease, schizoaffective disorder, schizotypal disorder, obsessive-compulsive disorder, PTSD, anorexia nervosa, panic disorder, attention-deficit hyperactivity disorder (ADHD), or dysthymic disorder.

[0086] Embodiment 18. The method of embodiment 10, wherein said neuropsychiatric disorder is an epileptic disorder.

[0087] Embodiment 19. The method of embodiment 18, wherein said epileptic disorder is epilepsy, chronic migraine with or without aura, migraine aura without headache, chronic tension headache, hemicrania continua, chronic headache including new onset daily persistent headache, post-stroke, dementia, multiple sclerosis, cancer, chronic pain, HIV / AIDs, lupus, or hypothyroidism.

[0088] Embodiment 20. The method of any one of embodiments 1 to 19, wherein Compound A is administered orally to said human.

[0089] Embodiment 21. The method of any one of embodiments 1 to 20, wherein Compound A is administered to said human at a dose of 2 to 200 mg.

[0090] Embodiment 22. The method of embodiment 20, wherein Compound A is administered to said human at a dose of 5 to 100 mg.

[0091] Embodiment 23. The method of embodiment 20, wherein Compound A is administered to said human at a dose of 5 to 80 mg.

[0092] Embodiment 24. The method of embodiment 20, wherein Compound A is administered to said human at a dose of 5 to 40 mg.

[0093] Embodiment 25. The method of any one of embodiments 1 to 20, wherein Compound A is administered to said human in a dose of at least 5 mg.

[0094] Embodiment 26. The method of embodiment 25, wherein Compound A is administered to said human in a dose of at least 10 mg.

[0095] Embodiment 27. The method of embodiment 25, wherein Compound A is administered to said human in a dose of at least 20 mg.

[0096] Embodiment 28. The method of any one of embodiments 1 to 20, wherein Compound A is administered to said human at a dose of 5 to 1000 mg per day or per week.

[0097] Embodiment 29. The method of embodiment 28, wherein Compound A is administered to said human in a dose of 5 to 500 mg per day or per week.

[0098] Embodiment 30. The method of embodiment 28, wherein Compound A is administered to said human at a dose of 5 to 250 mg per day or per week.

[0099] Embodiment 31. The method of embodiment 28, wherein Compound A is administered to said human at a dose of 5 to 150 mg per day.

[0100] Embodiment 32. The method of embodiment 28, wherein Compound A is administered to said human being at a dose of 100 mg per day.

[0101] Embodiment 33. The method of any one of embodiments 1 to 32, wherein Compound A is administered to said human at a dose of 0.05 to 20 mg / kg.

[0102] Embodiment 34. The method of embodiment 33, wherein Compound A is administered to said human at a dose of 0.1 to 5 mg / kg.

[0103] Embodiment 35. The method of any one of embodiments 1 to 34, wherein Compound A is orally administered to said human between about 30 minutes prior to ingestion of a meal and about 2 hours after ingestion of a meal.

[0104] Embodiment 36. The method of embodiment 35, wherein Compound A is orally administered to said human during a meal or within 15 minutes of ingesting a meal.

[0105] Embodiment 37. The method of any one of embodiments 1 to 36, wherein said anhedonia prior to treatment with Compound A has a severity of at least 5 as measured by the Snaith-Hamilton Pleasure Scale (SHAPS).

[0106] Embodiment 38. The method of embodiment 37, wherein said anhedonia prior to treatment with Compound A has a severity of at least 9 as measured by SHAPS. EXAMPLES

[0107] Studies were conducted to determine the effects of Compound A in rodent models of anhedonia, such as the Progressive Ratio Test (PRT). Further studies will be conducted to determine the effects, if any, of Compound A in acceptable models of anhedonia.

[0108] 1. Example 1. Effects of Compound A on motivation in rats trained to respond for available food under a progressive schedule of reinforcement The purpose of this study was to test the effects of Compound A (1, 3, or 8 mg / kg, orally) on motivation as measured by rats responding for food under a progressive ratio (PR) schedule of reinforcement. Test measures included total number of lever presses and number of rewards (food pellets) obtained (breakpoint).

[0109] 1.1. Introduction The progressive ratio (PR) task is an interspecies translational (bridging) approach used as a measure of motivational capacities, including as a measure of anhedonia (e.g., Hodos W., Science 1961, 134:943-944; Spierling et al., Physiol Behav. 2017, 177:99-106; Radke et al., Pharmacol Biochem Behav. 2015, 129:51-55; Hauser et al., Hormones and Behavior 2009, 56:364-375; Merali et al., Psychopharmacology 2003, 165:413-418; Marchese et al., Int J Neuropsychopharmacology 2013, 16:1611-1621; Karlsson et al., Hippocampus 2018, 28(7):512-522; see Strauss et al., Schizophr Res. 2016, 170(1):198-204; and Gunthorpe et al., Epilepsia 2012, 53(3):412-424). In rodent species, the basic test design involves training subjects to lever press for a food reward (45 mg Bioserve pellets) under a schedule in which the number of responses required to achieve a pellet increases for successive reinforcers. This study used a ratio = [5 × e (0.2×強化子数) We used progressive ratios derived from the formula [Eq. (10)-5] and were as follows: 2, 4, 6, 9, 12, 15, 20, 25, 32, 40, 50, 62, 77, 95, 118, 145, 178, etc. Therefore, rats were required to press the lever a progressively increasing number of times to obtain each successive reward until they reached a breaking point, i.e., no longer met the schedule requirements. A breaking point was determined when the rat failed to obtain a pellet over a 20-min period. This provided a quantitative measure of the effort an animal would expend on a given reinforcer, which we interpreted as a measure of motivation. Based on the amount of food obtained during a typical test session (e.g., a breaking point of 10–12 corresponds to 0.45–0.54 g of food), responding is limited by the amount of effort an animal is willing to expend on a single food pellet, rather than factors such as satiety.

[0110] Rats may be classified based on the difference in PR breakpoints, i.e., "low" and "high" responder rats. Importantly, "low" responder rats are not characterized by signs of poor health (e.g., weight loss) or sensorimotor impairments, but rather show greater motivational anhedonia as measured by PRT. Motivational deficits are commonly seen in anhedonia associated with many neuropsychological disorders, such as depression, dementia, and schizophrenia (Lactot et al., Alzheimer's and Dementia 2017, 13:84-100), and efficacy in treating "low" responder rats indicates efficacy in treating more severe or severe anhedonia.

[0111] The primary objective of this proposal was to evaluate the effect of Compound A on the motivational abilities of male Long Evans rats under a progressive ratio schedule. Using a large (N=32) cohort of rats, the effect of Compound A was examined in both all rats and in a subgroup of "low" responding rats based on a low tertile (N=11) cohort recorded over a 5-day period of baseline responding prior to the start of the study.

[0112] 1.2. Research Schedule: [Table 1]

[0113] 1.3. Experimental materials Drugs examined

[0114] 1.3.1. Compound A (Lot No. 12) Dosage Form: Compound A was suspended in 0.5% CMC-Na and 0.1% Tween 80 in purified water and sonicated until completely dissolved. The drug was administered orally at a volume of 10 mL / kg. Doses tested: 1, 3, 8 mg / kg. Pretreatment time: 120 minutes.

[0115] 1.3.2. D-Amphetamine (Lot No. 11-MWC-62-1) Dosage Form: D-Amp was suspended in 0.9% saline and sonicated until completely dissolved. The drug was administered intraperitoneally at a volume of 1 mL / kg. Dose tested: 0.6mg / kg. Pretreatment time: 10 minutes.

[0116] 1.4. Materials and Methods Test system: Thirty-two experimentally non-naive male Long Evans rats were included in the study.

[0117] Selection and allocation of animals: All animals were free of overt signs of ill health and were deemed satisfactory for the purposes of the study.

[0118] Husbandry and Care of the Test System: Animals were housed singly and maintained on a restricted diet regimen in which they were fed approximately 18-20 g of standard laboratory chow once per day after completion of the testing procedures (between 16:00 and 18:00 h). Water was available ad libitum, except during training / testing sessions. Animals were maintained on a 12-h / 12-h light / dark cycle, and all testing was performed during the animals' light cycle. All animal use procedures were performed in accordance with the principles of the Canadian Council on Animal Care (CCAC).

[0119] Progressive ratio schedule: Drug testing was performed according to a repeated measures design, with each animal receiving each treatment over repeated test sessions. Thirty-two experimentally non-naive male Long Evans rats were studied.

[0120] Compound A was tested under a PR schedule at three doses, as outlined in Table 2, along with a vehicle control (0.5% CMC and 0.1% Tween 80 in purified water) and a reference control (D-amphetamine 0.6 mg / kg, ip) (i.e., 5 cycles). During the intervening weekdays, all rats continued to train under standard conditions to maintain performance. Drug testing was performed twice weekly with a 3-4 day washout period between treatment sessions. As a result, drug testing took approximately 3 weeks to complete.

[0121] [Table 2]

[0122] Statistical Analysis: The primary measures of performance from the PR schedule (i.e., number of lever presses, number of rewards obtained (breakpoint), and session duration) were expressed as mean and SEM. Data from each measure were analyzed by one-way repeated measures ANOVA (Statistica Version 11, Statsoft Inc., 2012). Animals were also ranked based on their performance measured over a 7-day period prior to the start of testing. Based on this ranking, animals were classified as either "low" responding rats (i.e., low tertile, N = 11) or "high" responding rats (i.e., high tertile, N = 11), and each performance measure was assessed by a two-way mixed factorial ANOVA (treatment: within; subgroup: between) (Statistica Version 11, Statsoft Inc., 2012). The middle tertile was excluded from subgroup analyses. A logarithmic transformation was also performed on the lever pressing data to reduce the skewed data distribution to normality. In case of significant main effects, planned post-hoc comparisons between vehicle and treatment groups were performed (Dunnetts or LSD tests). Significance was set at P<0.05.

[0123] 1.5. Results Analysis of all rats (N=32): vehicle and Compound A (1, 3 and 8 mg / kg) groups revealed significant main effects for lever pressing (F3,93=5.6; P<0.01) and breaking point (F3,93=6.6; P<0.01). Subsequent Dunnett's tests revealed significant increases in both measures after Compound A (3 and 8 mg / kg) pretreatment compared to vehicle. For reference, all rats received an additional pretreatment of D-amphetamine (0.6 mg / kg, ip). D-amphetamine produced significant increases in both lever pressing (Veh: 334+38; AMP: 893+131; P<0.01 paired T-test) and breaking point (Veh: 11.5+0.5; AMP: 14.7+0.7; P<0.01 paired T-test) compared to vehicle pretreatment. See Figure 1 and Tables 3-5.

[0124] [Table 3]

[0125] [Table 4]

[0126] [Table 5]

[0127] "High" vs. "Low" responding rat subgroups (N=11 / subgroup): For both lever pressing and breaking point measures, a two-way ANOVA revealed a main effect of subgroup (F1,20 ≥ 25.1; P < 0.01) reflecting an overall difference in food-maintained responding between the two extreme subgroups. For lever pressing measures, there was no main effect of treatment (F3,60 = 2.0; P = 0.13; NS) or treatment × subgroup interaction (F3,60 = 1.7; P = 0.17; NS), but after log transformation, a main effect of treatment (F3,60 = 4.2; P < 0.01) and treatment × subgroup interaction (F3,60 = 4.7; P < 0.01) were recorded. This reflected the effect of Compound A (3 and 8 mg / kg) pretreatment to selectively increase the number of lever presses in the "low" responding rat cohort. For the scale breakpoints, a main effect of treatment (F3,60 = 3.3; P = 0.03) and a treatment × subgroup interaction (F3,60 = 3.6; P = 0.02) further supported the effect of Compound A (3 and 8 mg / kg) in selectively increasing responding for food in the "low" responding rat cohort. D-amphetamine produced significant increases in lever presses and breakpoints compared to vehicle pretreatment in both the "low" and "high" responding rat subgroups (e.g., breakpoints: "low" responding rats: Veh: 9.2 ± 0.6; AMP: 12.2 ± 1.2; P < 0.01; "high" responding rats: 14.0 ± 0.6; AMP: 17.5 ± 0.9; P < 0.01). See Figure 2 and Tables 6-8.

[0128] [Table 6]

[0129] [Table 7]

[0130] [Table 8]

[0131] [Table 9]

[0132] [Table 10]

[0133] Conclusion This study was designed to examine the effects of Compound A (1, 3 and 8 mg / kg, orally) on motivation for food made available under a progressive ratio (PR) schedule of reinforcement. D-amphetamine (0.6 mg / kg, ip) was included for reference. A relatively large (N=32) cohort of rats was used in this study, and the effects of Compound A were examined in all rats and also in a "low" responding rat subgroup based on responses measured over a 5-day baseline prior to the start of the study. The "low" responding rat subgroup model represents a low motivation / anhedonia behavioral phenotype with significantly lower motivation / greater decision anhedonia than the "high" responding rat group.

[0134] Robust effects of Compound A were found on both lever pressing and breaking points, with oral doses of 3 and 8 mg / kg significantly increasing both measures compared to vehicle pretreatment. Analysis of the "high" and "low" responding rat subgroups identified the effect of Compound A as statistically significant in the "low" responding rat subgroup. The effect of Compound A differed from D-amphetamine in two ways: (1) the magnitude of the increase, and (2) the effect of Compound A only showed statistical significance in the "low" responding rats. This may suggest a more subtle effect of Compound A on CNS systems related to reward / motivation compared to D-amphetamine.

[0135] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned herein, including U.S. Provisional Application No. 63 / 147,742, filed February 9, 2021, are hereby incorporated by reference in their entireties.

[0136] Although the above compositions, methods, and uses have been described in some detail for ease of understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims. Accordingly, the described embodiments are to be considered as illustrative rather than restrictive, and the claimed invention is not to be limited to the details given herein, but may be modified within the scope and equivalents of the appended claims.

Claims

1. 1. An agent for use in treating anhedonia in a human in need thereof, said treatment comprising administering to said human a therapeutically effective amount of said agent; The agent for use is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide.

2. 1. An agent for use in reversing hyperactivity in the ventral tegmental area (VTA) in a human in need thereof, said reversing comprising administering to said human an effective amount of said agent; The agent is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, The method of claim 1, wherein the human is suffering from anhedonia.

3. 3. The method of claim 1, comprising enhancing the opening of Kv7 potassium channels in said human.

4. 1. An agent for use in enhancing the opening of a Kv7 potassium channel in a human, said enhancing comprising the step of administering to said human an effective amount of said agent; The agent is N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethylphenyl]-3,3-dimethylbutanamide, The method of claim 1, wherein the human is suffering from anhedonia.

5. 5. The agent for use according to claim 3 or claim 4, wherein the Kv7 potassium channel is one or more of Kv7.2, Kv7.3, Kv7.4 or Kv7.5, and the use may be selective for enhancing the opening of one or more of Kv7.2, Kv7.3, Kv7.4 or Kv7.5 over Kv7.

1.

6. 5. An agent for use according to claim 3 or claim 4, which comprises the opening of Kv7.2 / Kv7.3 (KCNQ2 / 3) potassium channels.

7. The anhedonia may be (i) including sexual anhedonia, (ii) includes social anhedonia; and / or (iii) is a symptom of a neuropsychiatric disorder Agent for use according to any one of claims 1 to 6.

8. 8. The method of claim 7, wherein the neuropsychiatric disorder is a depressive disorder, a substance-related disorder, a psychotic disorder, a personality disorder, an epileptic disorder, or a combination thereof.

9. 9. The agent for use according to claim 8, wherein the psychoneurological disorder is a depressive disorder, and the depressive disorder may be stress-induced depression, major depressive disorder (MDD), post-traumatic stress disorder (PTSD), severe mood dysregulation disorder, persistent depressive disorder, bipolar spectrum disorder, bipolar depression, postpartum depression, premenstrual dysphoric disorder (PMDD), seasonal affective disorder (SAD), atypical depression, treatment-resistant depression (TRD), depression associated with agitation or anxiety, adjustment disorder with depressed mood, prolonged depressive reaction, or a combination thereof, and the depressive disorder may be MDD.

10. 9. The method of claim 8, wherein the neuropsychiatric disorder is a substance-related disorder, and the substance-related disorder may include an addiction to alcohol, cocaine, opioids, or nicotine.

11. 9. The agent for use according to claim 8, wherein the psychoneurological disorder is schizophrenia, extrapyramidal disorder, Alzheimer's disease, dementia, Parkinson's disease, schizoaffective disorder, schizotypal disorder, obsessive-compulsive disorder, PTSD, anorexia nervosa, panic disorder, attention deficit hyperactivity disorder (ADHD), or dysthymic disorder, and the psychoneurological disorder may be an epileptic disorder.

12. 9. The agent for use according to claim 8, wherein the epileptic disorder is epilepsy, chronic migraine with or without aura, migraine aura without headache, chronic tension headache, hemicrania continua, chronic headache including new onset persistent daily headache, post-stroke, dementia, multiple sclerosis, cancer, chronic pain, HIV / AIDs, lupus, or hypothyroidism.

13. The agent for use according to any one of claims 1 to 12, wherein the agent is orally administered to the human.

14. (i) the agent is administered to the human at a dose of 5 to 100 mg, the agent comprising: (a) administering to the human 5 to 80 mg; (b) 5 to 40 mg to the human; (c) administering 10 to 30 mg to the human; or (d) administering 10, 15, 20, 25, 30, or 35 mg to the human and / or (ii) the agent is administered to the human at a dose of 5 to 100 mg per day, the agent comprising: (a) administering to the human between 5 and 80 mg per day; (b) 5 to 40 mg per day to the human; (c) administering to the human 10 to 30 mg per day; or (d) administering 10, 15, 20, 25, 30, or 35 mg per day to the human may be administered at a dose of Agent for use according to any one of claims 1 to 13.

15. The method of claim 1, wherein the agent is administered orally as a single dose of 10 to 30 mg per day.

16. The method of claim 1, wherein the agent is administered to the human at a dose of 0.05 to 20 mg / kg, and the agent may be administered to the human at a dose of 0.1 to 5 mg / kg.

17. An agent for use as described in any one of claims 1 to 16, wherein the agent is orally administered to the human between about 30 minutes prior to and about 2 hours after ingestion of a meal, and the agent may be orally administered to the human during a meal or within 15 minutes after ingestion of a meal.

18. The agent for use according to any one of claims 1 to 17, wherein the anhedonia prior to treatment with the agent has a severity of at least 5 as measured by the Snaith-Hamilton Pleasure Scale (SHAPS), and optionally the anhedonia prior to treatment with the agent has a severity of at least 9 as measured by the SHAPS.

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