Uses of AVPR1A agonists

Abstract

An AVPR1A agonist for use in treating a subject suffering from or at risk of (i) a nervous system disease or disorder, or (ii) an inflammatory disease or disorder, or (b) improving sleep in a subject, or (c) improving cognition in a subject. The peptide LSSTQAQQSY (SEQ ID NO: 1) is useful for treating psychiatric disorders such as mood disorders, anxiety disorders, and reduced motivation disorders. The present disclosure is based, in part, on the identification of the putative biological target of LSSTQAQQSY (SEQ ID NO: 1), arginine vasopressin receptor 1A (AVPR1A).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application Nos. 63 / 387,418 (filed December 14, 2022) and 63 / 507,754 (filed June 13, 2023), the disclosures of each of which are incorporated herein by reference in their entirety for all purposes.

[0002] Sequence Listing This specification references a Sequence Listing that has been submitted electronically in XML format, which is incorporated herein by reference in its entirety. The XML file, created on December 14, 2023, is named DGS-007WO_ST26 and is 2kb in size. [Background technology]

[0003] It is estimated that 9.5% of the adult population in the United States suffers from a mood disorder (Kessler et al., 2005, Arch Gen Psychiatry 62(6):617-627). Only about half of people with a mood disorder receive treatment, and of those who do, fewer than 40% receive minimally adequate treatment (Wang et al., 2005, Arch Gen Psychiatry 62(6):629-640).

[0004] It is also estimated that anxiety disorders affect 18.1% of the adult population in the United States (Kessler et al., 2005, Arch Gen Psychiatry 62(6):617-627). Fewer than 40% of people with anxiety disorders receive treatment, and of those who do, fewer than 35% receive minimally adequate treatment (Wang et al., 2005, Arch Gen Psychiatry 62(6):629-640). Motivational deficits frequently occur in individuals with traumatic brain injury, with estimates of their prevalence varying from 5% to 67% (Marin and Wilkosz, 2005, J Head Trauma Rehabil 20(4):377-388). Motivational deficits are also frequently seen in individuals with depression, Parkinson's disease, Alzheimer's disease, and schizophrenia, as well as those who have had a stroke and in healthy individuals, particularly older adults (Bonnelle et al., 2015, Journal of Physiology 109:16-26). [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Kessler et al., 2005, Arch Gen Psychiatry 62(6):617-627 [Non-patent document 2] Wang et al., 2005, Arch Gen Psychiatry 62(6):629-640 [Non-patent document 3] Marin and Wilkosz,2005,J Head Trauma Rehabilitation 20(4):377-388 [Non-patent document 4] Bonnelle et al.,2015,Journal of Physiology 109:16-26 Summary of the Invention

[0006] The peptide LSSTQAQQSY (SEQ ID NO: 1) is useful for treating psychiatric disorders such as mood disorders, anxiety disorders, and reduced motivation disorders. The present disclosure is based, in part, on the identification of arginine vasopressin receptor 1A (AVPR1A), a putative biological target of LSSTQAQQSY (SEQ ID NO: 1). LSSTQAQQSY (SEQ ID NO: 1) is believed to mediate its therapeutic effects by agonizing AVPR1A. Furthermore, indications suitable for treatment with LSSTQAQQSY (SEQ ID NO: 1) are believed to be similarly suitable for treatment with other AVPR1A agonists, such as vasopressin, natural AVPR1A ligands, and synthetic AVPR1A agonists, such as vasopressin analogs, including desmopressin, terlipressin, and felypressin.

[0007] The present disclosure is also based, in part, on new insights into the biological activity of LSSTQAQQSY (SEQ ID NO: 1). Specifically, it has been surprisingly discovered that peptide LSSTQAQQSY (SEQ ID NO: 1) has biological activities beyond those previously reported. For example, microdialysis studies performed with peptide LSSTQAQQSY (SEQ ID NO: 1), as detailed in the Examples, demonstrated that oral administration of this peptide surprisingly affects the levels of certain neurotransmitters in the brain, including histamine and norepinephrine. Without being bound by theory, these neurotransmitters are believed to be associated with various diseases, disorders, and conditions, such as schizophrenia and neurodegenerative diseases (e.g., Parkinson's disease), particularly the negative symptoms associated with these diseases. Furthermore, studies performed with peptide LSSTQAQQSY (SEQ ID NO: 1) in a lipopolysaccharide-induced inflammation model, also detailed herein, demonstrated that oral administration of this peptide surprisingly suppressed the release of the pro-inflammatory cytokine TNF-α, which is associated with various diseases, including rheumatoid arthritis and inflammatory bowel disease. Furthermore, studies conducted in human subjects using the peptide LSSTQAQQSY (SEQ ID NO: 1), also detailed in the Examples, demonstrated that oral administration of this peptide provided cognitive-enhancing effects. Thus, the studies described in the Examples demonstrate that LSSTQAQQSY (SEQ ID NO: 1) and other AVPR1A agonists can be used to treat a variety of diseases, disorders, and conditions.

[0008] In some embodiments, the present disclosure provides methods of treating diseases, disorders, and conditions amenable to treatment by vagus nerve stimulation and / or modulation of histamine and / or norepinephrine levels and / or modulation of TNF-α with AVPR1A agonists.

[0009] In some embodiments, the present disclosure provides (a) a method of treating a subject suffering from or at risk of (i) a disease or disorder of the nervous system or (ii) an inflammatory disease or disorder, or (b) a method of improving sleep in a subject, or (c) a method of improving cognition in a subject, comprising administering to the subject a therapeutically effective amount of an AVPR1A agonist.

[0010] In some embodiments, the present disclosure provides (a) a method of treating a subject suffering from or at risk for (i) a disease or disorder of the nervous system or (ii) an inflammatory disease or disorder, or (b) a method of improving sleep in a subject, or (c) a method of improving cognition in a subject, comprising administering to the subject an agent comprising a means for agonizing arginine vasopressin receptor 1A (AVPR1A).

[0011] Exemplary diseases and disorders that can be treated with AVPR1A agonists include inflammatory diseases and disorders, schizophrenia, psychosis, neurodegenerative diseases, gastrointestinal diseases and disorders, pain, rheumatoid arthritis, migraine, headache, substance abuse, drug addiction, seizure disorders, major depressive disorder, atypical depression, major depressive episode (MDE), treatment-resistant depression, depression in the presence of neurodegenerative disease, cognitive impairment, COVID-19 associated cognitive impairment and / or COVID-19 associated depression, ADHD, autism spectrum disorder, pervasive developmental disorder, atypical autism, multiple sclerosis, PTSD, and sleep disorders.

[0012] Exemplary AVPR1A agonists include vasopressin analogs, such as felypressin or desmopressin.

[0013] In some embodiments, the methods provided are used to treat a subject suffering from or at risk for Alzheimer's disease or Parkinson's disease.

[0014] In some embodiments, the methods provided are used to improve cognition.

[0015] In some embodiments, the methods provided are used to improve cognition.

[0016] In some embodiments, the methods provided are used to treat a subject suffering from or at risk for depression.

[0017] In some embodiments, the present disclosure provides a method of treating a subject suffering from or at risk of Alzheimer's disease or Parkinson's disease, comprising administering to the subject a therapeutically effective amount of a vasopressin analog or a pharmaceutically acceptable salt thereof.

[0018] In some aspects, the present disclosure provides a method of improving cognition in a subject, the method comprising administering to the subject a therapeutically effective amount of a vasopressin analog or a pharmaceutically acceptable salt thereof.

[0019] In some aspects, the present disclosure provides a method for improving sleep in a subject, the method comprising administering to the subject a therapeutically effective amount of a vasopressin analog or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the present disclosure provides a method of treating a subject having or at risk of having depression, the method comprising administering to the subject a therapeutically effective amount of a vasopressin analog or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, the subject is a mammal, for example a human.

[0022] In some embodiments, the vasopressin analog is felypressin or desmopressin.

[0023] In some embodiments, the AVPR1A agonist or AVPR1A agent is administered multiple times, for example, more than once per day, or once per day for more than one day.

[0024] In a further aspect, the present disclosure provides AVPR1A agonists for use in the methods of treatment described herein.

[0025] In a further aspect, the present disclosure provides the use of an AVPR1A agonist in the manufacture of a medicament for treating a subject having or at risk of developing a disease or condition disclosed herein.

[0026] Exemplary features of methods of treatment, compounds and compositions for use in the methods of treatment, and uses are described in the detailed description and numbered embodiments 1-104 below. [Brief explanation of the drawings]

[0027] [Figure 1] FIG. 1 shows that the AVPR1A / AVPR2 inhibitor conivaptan blocks the activity of LSSTQAQQSY (SEQ ID NO: 1) (reduction of TST immobility) in the tail suspension test (Example 1). [Figure 2] FIG. 1 shows that low doses of the AVPR1A / AVPR2 inhibitor conivaptan block the activity of LSSTQAQQSY (SEQ ID NO: 1) (reduction of TST immobility) in the tail suspension test (Example 1). [Figure 3] FIG. 1 shows that the AVPR2 inhibitor tolvaptan does not block the activity of LSSTQAQQSY (SEQ ID NO: 1) (reduction of TST immobility) in the tail suspension test (Example 1). [Figure 4] FIG. 1 shows that the AVPR1A / B inhibitor nerivaptan blocks the activity of LSSTQAQQSY (SEQ ID NO: 1) (reduction of TST immobility) in the tail suspension test (Example 1). [Figure 5A] FIG. 1 shows levels of the neurotransmitter histamine in the prefrontal cortex of mice before and after oral administration of LSSTQAQQSY (SEQ ID NO: 1) (Example 2). [Figure 5B]FIG. 1 shows levels of the neurotransmitter norepinephrine in the prefrontal cortex of mice before and after oral administration of LSSTQAQQSY (SEQ ID NO: 1) (Example 2). [Figure 5C] FIG. 1 shows the levels of the neurotransmitter GABA in the prefrontal cortex of mice before and after oral administration of LSSTQAQQSY (SEQ ID NO: 1) (Example 2). [Figure 5D] FIG. 1 shows levels of the neurotransmitter glutamate in the prefrontal cortex of mice before and after oral administration of LSSTQAQQSY (SEQ ID NO: 1) (Example 2). [Figure 5E] FIG. 1 shows levels of the neurotransmitter glycine in the prefrontal cortex of mice before and after oral administration of LSSTQAQQSY (SEQ ID NO: 1) (Example 2). [Figure 5F] FIG. 1 shows levels of the neurotransmitter dopamine in the prefrontal cortex of mice before and after oral administration of LSSTQAQQSY (SEQ ID NO: 1) (Example 2). [Figure 5G] FIG. 1 shows levels of the neurotransmitter serotonin in the prefrontal cortex of mice before and after oral administration of LSSTQAQQSY (SEQ ID NO: 1) (Example 2). [Figure 6A] FIG. 1 shows the levels of the neurotransmitter histamine in the striatum of mice before and after oral administration of LSSTQAQQSY (SEQ ID NO: 1) (Example 2). [Figure 6B] FIG. 1 shows levels of the neurotransmitter norepinephrine in the mouse striatum before and after oral administration of LSSTQAQQSY (SEQ ID NO: 1) (Example 2). [Figure 6C] FIG. 1 shows the levels of the neurotransmitter GABA in the striatum of mice before and after oral administration of LSSTQAQQSY (SEQ ID NO: 1) (Example 2). [Figure 6D] FIG. 1 shows the levels of the neurotransmitter glutamate in the mouse striatum before and after oral administration of LSSTQAQQSY (SEQ ID NO: 1) (Example 2). [Figure 6E] FIG. 1 shows the levels of the neurotransmitter glycine in the striatum of mice before and after oral administration of LSSTQAQQSY (SEQ ID NO: 1) (Example 2). [Figure 6F] FIG. 1 shows the levels of the neurotransmitter dopamine in the striatum of mice before and after oral administration of LSSTQAQQSY (SEQ ID NO: 1) (Example 2). [Figure 6G] FIG. 1 shows the levels of the neurotransmitter serotonin in the mouse striatum before and after oral administration of LSSTQAQQSY (SEQ ID NO: 1) (Example 2). [Figure 7] FIG. 1 shows plasma TNF-α levels after administration of lipopolysaccharide and peptide LSSTQAQQSY (SEQ ID NO: 1) (Example 3). [Figure 8] (FIG. 8A) Study design for single ascending dose cohorts S1, S2, S3, and S4 in a Phase 1 clinical trial of peptide LSSTQAQQSY (SEQ ID NO: 1). (See Example 4.) (FIG. 8B) Study design for multiple ascending dose (MAD) cohort 1 in a Phase 1 clinical trial of peptide LSSTQAQQSY (SEQ ID NO: 1). (See Example 4.) (FIG. 8C) Study design for MAD cohort 2 in a Phase 1 clinical trial of peptide LSSTQAQQSY (SEQ ID NO: 1). (See Example 4.) [Figure 9] FIG. 1 shows the effect of doses of 60 mg / day (MAD1), 180 mg / day (MAD2), or 540 mg / day (MAD3) versus placebo on the global outcome of the PHQ-9 questionnaire (Example 4). [Figure 10] FIG. 1 shows the effect of doses of 60 mg / day (MAD1), 180 mg / day (MAD2), or 540 mg / day (MAD3) versus placebo on the CogState Detection Test (DET) of psychomotor function (Example 4). [Figure 11]FIG. 1 shows the effect of doses of 60 mg / day (MAD1), 180 mg / day (MAD2), or 540 mg / day (MAD3) versus placebo on the CogState Groton Maze Test (GMLT) of executive function (Example 4). [Figure 12] FIG. 1 shows the effect of doses of 60 mg / day (MAD1), 180 mg / day (MAD2), or 540 mg / day (MAD3) versus placebo on the CogState Identification Test of Attention (IDN) (Example 4). [Figure 13A] 1 shows the composite cognitive scores in the placebo and peptide-treated groups of MAD Cohort 2 (crossover study) on Day 1 (pre-dose) and Day 7 (4 hours post-dose) in a Phase 1 clinical trial (see Example 4). [Figure 13B] 1 shows radar plots for four Cogstate tests: detection test (DET), Groton Maze Learning (GMLT), Identification test (IDN), and One Card Learning test (OCL) for 13 subjects in MAD Cohort 2 of a Phase 1 clinical trial (see Example 4). [Figure 13C] Figure 1 shows test scores for four tests in placebo-treated subjects (leftmost bar in each pair of bars for each test) and peptide-treated subjects (rightmost bar in each pair of bars for each test) (see Example 4). [Figure 14] Figure 1 shows theta power (top panel) and alpha power (bottom panel) across multiple dose levels in MAD Cohort 1 in a Phase 1 clinical trial (see Example 4). [Figure 15] Figure 1 shows the modulation of alpha power in the eyes-open state across multiple dose levels in MAD Cohort 1 in a Phase 1 clinical trial (see Example 4). [Figure 16A]FIG. 1 shows dose-dependent insomnia sleep index (ISI) values ​​for MAD Cohort 1 in a Phase 1 clinical trial (n=6 per dose, p=0.04 (peptide treatment group vs. placebo group) based on a one-tailed Mann-Whitney t-test). (See Example 4.) [Figure 16B] FIG. 1 shows ISI values ​​at 4 hours post-dose on Days 1, 7, and 7 for placebo- and peptide-treated subjects in MAD Cohort 1 in a Phase 1 clinical trial. [Figure 16C] Figure 1 shows ISI values ​​for placebo-treated and peptide-treated subjects in MAD Cohort 2 of a Phase 1 clinical trial at days 1, 7, and 4 hours post-dose on day 7. The p-value for Day 1 vs. Day 7 (4 hours post-dose) was 0.03 for Cohort 1 (n=6), 0.1 for Cohort 2 (n=11), and 0.01 for Cohorts 1+2. (See Example 4.) [Figure 17A] Figure 1 shows the alpha slow wave index (ASI; alpha / (delta+theta)) in the frontal cortex plotted against the dose of peptide administered in a phase 1 clinical trial. [Figure 17B] Figure 1 shows insomnia severity scores (y-axis) on day 7 plotted against ASI changes in the frontal cortex (Fz eyes closed) (x-axis) in subjects treated with peptides in a Phase 1 clinical trial (see Example 4). [Figure 18] 1 shows the effect of orally administered felypressin (0.03 mg / kg, 0.1 mg / kg, and 0.3 mg / kg) and LSSTQAQQSY (SEQ ID NO: 1) (0.3 mg / kg) in the mouse tail suspension test (Example 5). Mean ± SEM (n=6). [Figure 19] 1 shows the effects of orally administered felypressin (0.1 mg / kg), conivaptan (3 mg / kg), and felypressin (0.1 mg / kg) + conivaptan (3 mg / kg) in the mouse tail suspension test (Example 5). Mean ± SEM (n=7). [Figure 20]1 shows the effects of orally administered desmopressin (0.03 mg / kg, 0.1 mg / kg, and 0.3 mg / kg) and felypressin (0.1 mg / kg) in the mouse tail suspension test (Example 6). Mean ± SEM (n=6). [Figure 21] 1 shows the effects of orally administered desmopressin (0.1 mg / kg, 0.3 mg / kg, 1.0 mg / kg) and felypressin (0.1 mg / kg) in the mouse tail suspension test (Example 6). Mean ± SEM (n=6). [Figure 22] FIG. 1 shows immobility time (indicating stress resilience) in mice administered vehicle or 0.03 mg / kg, 0.3 mg / kg, 3 mg / kg, or 10 mg / kg of the peptide (LSSTQAQQSY (SEQ ID NO: 1)) followed by the tail suspension test (TST). [Figure 23A] FIG. 1 shows immobility time in mice subjected to the tail suspension test (TST) after administration of vehicle, 1 mg / kg peptide (LSSTQAQQSY (SEQ ID NO: 1)) once, or 0.3 mg / kg peptide once, twice, or three times at 2-hour intervals. [Figure 23B] FIG. 1 shows immobility time in mice subjected to the tail suspension test (TST) after daily administration of vehicle or peptide (LSSTQAQQSY (SEQ ID NO: 1)) for 1 or 5 days. DETAILED DESCRIPTION OF THE INVENTION

[0028] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. For a full understanding of the terms used herein, the following definitions are provided:

[0029] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "an agent" includes multiple agents (including mixtures thereof).

[0030] Unless otherwise indicated, the conjunction "or" is intended to be used in its proper sense as a Boolean logic operator, encompassing both alternative selection of features (A or B, where selection of A is mutually exclusive with B) and simultaneous selection of features (A or B, where both A and B are selected). In some places in the text, the term "and / or" is used for the same purpose, but this should not be construed to imply that "or" is used in reference to mutually exclusive alternatives.

[0031] As used herein, the term "AVPR1A" refers to arginine vasopressin receptor 1A. Exemplary AVPR1A. An exemplary AVPR1A sequence is available in the Uniprot database under accession number P37288.

[0032] As used herein, the term " negative symptom " refers to the inability of subject to perform normal function.For example, the examples of negative symptoms in subjects suffering from schizophrenia include antisociality, anhedonia, allopathic, flat affect, apathy, apathy, blunted affect, anergy, depression, low mood and cognitive impairment.Negative symptoms, such as one or more of the negative symptoms, can also be experienced by subjects suffering from other diseases, for example, subjects with neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease or ALS.The common negative symptoms in such subjects include anhedonia, apathy, depression and cognitive impairment.

[0033] As used herein, the " non-motor symptoms " of Parkinson's disease refers to the symptoms that are not related to movement.Non-motor symptoms include, for example, cognitive symptoms such as mood swings, depression, anxiety, panic attacks, fatigue, confusion and slowing of thinking, sensory symptoms such as numbness, restlessness, pain, chest discomfort and loss of smell, and autonomic symptoms such as hot / cold sensation, bladder abnormality, sweating, abdominal discomfort, constipation, salivation, frequent urination and / or urgency and erectile dysfunction.

[0034] As used herein, the terms "treat," "treatment," and "treating" refer to the reduction or amelioration of the progression or severity of one or more symptoms (preferably one or more identifiable symptoms) of a disease, disorder, or condition resulting from the administration of a compound or composition of the present disclosure (for the avoidance of doubt, each AVPR1A agonist disclosed herein is considered a compound of the present disclosure, and a pharmaceutical composition comprising such an AVPR1A agonist is considered a composition of the present disclosure). In certain embodiments, the terms "treat," "treatment," and "treating" refer to the improvement of at least one measurable physical parameter of a disease, disorder, or condition. In another embodiment, the terms "treat," "treatment," and "treating" refer to slowing the progression of one or more symptoms of a disease, disorder, or condition.

[0035] Means for activating AVPR1A Agents suitable for use in the methods of the present invention generally include a means for agonizing AVPR1A, including, for example, AVPR1A agonists, as described herein.

[0036] AVPR1A agonists AVPR1A agonists include peptides and non-peptide small molecules that bind to AVPR1A and trigger activation of downstream signaling pathways. In some embodiments, the AVPR1A agonists used in the methods and compositions of the present disclosure reversibly bind to AVPR1A. Although AVPR1A agonists preferably selectively bind to and activate AVPR1A, AVPR1A agonists need not be specific or selective for AVPR1A compared to other arginine-vasopressin receptors, such as AVPR1B and / or AVPR2, or the oxytocin receptor (OTR). In some embodiments, the AVPR1A agonists of the present disclosure selectively bind to and activate the AVPR1A receptor compared to AVPR1B and AVPR2. In some embodiments, the AVPR1A agonists of the present disclosure bind to and activate AVPR1A, and optionally AVPR1B and / or AVPR2 and / or OTR. In some embodiments, the AVPR1A agonist is a selective AVPR1A agonist, e.g., an agonist that has greater selectivity for AVPR1A over AVPR2, e.g., selepressin. The selectivity of agonists for different receptors can be assessed, for example, by comparing EC50 values.

[0037] An exemplary AVPR1A agonist is vasopressin, the natural ligand of AVPR1A. Thus, vasopressin can be used in the methods of the present disclosure. Vasopressin analogs can also be used. Exemplary vasopressin analogs include 1-desamino-8-D-arginyl vasopressin (desmopressin or DDAVP), 8-D-homoarginine vasopressin, felypressin, ornipressin, selepressin, triglyceride vasopressin (terlipressin), lypressin, F180 (Andres et al., 2002, Br. J. Pharmacol. 135(7):1828-36; Cotte et al., 2003, Eur. J. Biochem. 267, 4253-4263), and [deamino-Cys(1)]arginine vasopressin (dAVP). Analogs of the above can also be used. In some embodiments, the AVPR1A agonist is felypressin.

[0038] Exemplary vasopressin analogs have the general formula: [ka] and wherein X is (S)-2-amino-2-methyl-butanoic acid (CαMeAbu) or valine (Val); Y is thienylalanine (Thi) or methionine (Met), Z is D-phenylalanine (D-Phe) or D-thienylalanine (Thi) or D-tyrosine (D-Tyr), Asn is asparagine, Hyp is 4-trans-hydroxyproline, D-Arg is D-arginine, Gly is glycine.

[0039] Vasopressin analogs characterized by the above formula are described in PCT Publication No. WO 1995 / 000548 A1, which is incorporated by reference in its entirety.

[0040] Another exemplary vasopressin analog has the general formula: [ka] and wherein X is selected from the group consisting of H and NH; Y is selected from the group consisting of -SS-, -CHS-, and -SCH-; and (i) A=L and B=D, or (ii) A=D and B=L.

[0041] Vasopressin analogs characterized by the above formula are described in US Pat. No. 4,285,858, which is incorporated by reference in its entirety.

[0042] Another exemplary vasopressin analog has the general formula: [ka] and During the ceremony, R1 is H, R2 is CH2-S, and R3 is D-Arg, or R 1 is NH2 and R 2 is SS and R 3 is selected from D-Arg and L-Orn, and all other chiral amino acids belong to the L series.

[0043] Vasopressin analogs characterized by the above formula are described in US Pat. No. 4,482,486, which is incorporated by reference in its entirety.

[0044] Another exemplary vasopressin analog has the general formula: [ka] and During the ceremony, Ar is an aryl group selected from aromatic carbocyclic ring systems, 5- or 6-membered heteroaromatic ring systems, and bicyclic heteroaromatic ring systems; m is selected from 1, 2 and 3; n is selected from 0, 1, 2, 3 and 4; p is selected from 2, 3 and 4; R1, R2 and R3 are independently selected from H, OH, alkyl, O-alkyl and OC(O)-alkyl; alkyl is selected from C1-6 straight chain alkyl and C4-8 branched chain alkyl, and the alkyl may have at least one hydroxyl substituent; When n=0, R1 and R2 may together form a nitrogen-containing ring structure containing 2 to 5 carbon atoms; provided that when Ar is phenyl, m=2, n=0, R1=R2=H, R3 is not H, and p is 3 or 4.

[0045] Vasopressin analogs characterized by the above formula are described in US Pat. No. 8,222,202, which is incorporated by reference in its entirety.

[0046] Exemplary analogs of 8-D-homoarginine vasopressin are described in EP 0412508 (B1), which is incorporated by reference in its entirety.

[0047] In some embodiments, the AVPR1A agonist is a vasopressin analog or an analog of a vasopressin analog described in WO1995 / 000548A1, U.S. Pat. No. 4,285,858, U.S. Pat. No. 4,482,486, or U.S. Pat. No. 8,222,202, the contents of each of which are incorporated herein by reference in their entirety.

[0048] In some embodiments, the AVPR1A agonist is not a peptide or peptide conjugate disclosed in WO2016 / 140277 or WO2018 / 047852, the contents of each of which are incorporated herein by reference in their entirety.

[0049] Pharmaceutical Compositions In some embodiments, the present disclosure provides pharmaceutical compositions comprising the AVPR1A agonist described herein.Unless otherwise required by context, reference to a specific AVPR1A agonist should be understood to include the AVPR1A agonist and its pharmaceutically acceptable salts.Pharmaceutical compositions are preferably formulated for oral administration.Pharmaceutical compositions can be prepared according to standard methods in the art (for example, as described in Allen et al., eds., 2012, Remington: The Science and Practice of Pharmacy, 22nd edition, Pharmaceutical Press, London, UK).

[0050] In some embodiments, the present disclosure provides the use of an AVPR1A agonist, such as those described herein, in the manufacture of a medicament, such as for treating a subject having or at risk of a disease or condition described herein.

[0051] Treatment method AVPR1A agonists can be used to treat or prevent a variety of diseases, disorders, and conditions. The present disclosure provides therapeutic uses for AVPR1A agonists, including the treatment of diseases, disorders, and conditions amenable to treatment by vagus nerve stimulation and / or modulation of histamine and / or norepinephrine levels and / or modulation of the inflammatory cytokine TNF-α.

[0052] In some embodiments, the present disclosure provides a method for treating a subject suffering from or at risk of an inflammatory condition, comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.As will be understood by those skilled in the art, various conditions have inflammatory aspects and can be considered inflammatory conditions, such as, for example, inflammatory bowel disease, rheumatoid arthritis, and schizophrenia.

[0053] In some embodiments, the present disclosure provides a method for treating a subject suffering from or at risk of a disease or disorder of the nervous system (e.g., the central nervous system), comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0054] In some embodiments, the present disclosure provides a method for treating the subject suffering from or at risk of schizophrenia or psychosis, comprising administering to the subject an AVPR1A agonist in an amount effective for treating the subject.In some embodiments, the subject suffers from schizophrenia.In some embodiments, the subject exhibits psychotic behavior.

[0055] Schizophrenia is characterized by positive symptoms (e.g., delusions and hallucinations), negative symptoms, mood abnormalities, and cognitive deficits, often leading to severe functional impairment (Yasui-Furukori, 2012, Drug Des Devel Therapy 6:107-115). The treatment may involve, for example, improving or slowing the progression of one or more negative symptoms of schizophrenia or psychosis. Negative symptoms include antisociality, anhedonia, allopathic behavior, flat affect, apathy, amotivation, blunted affect, anergy, depression, low mood, and cognitive impairment. Cognitive impairment may be, for example, a deficit in verbal working memory, spatial working memory, verbal fluency, verbal learning, or a combination thereof. Negative symptoms, and changes in such symptoms, can be assessed using, for example, the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987, Schizophr Bull. 13(2):261-76), the Scale for the Assessment of Negative Symptoms (SANS) (Andreasen, 1982, Arch Gen Psychiatry 39(7):784-8), the Personal and Social Performance (PSP) scale (Morosini et al., 2000, Acta Psychiatr Scand. 101(4):323-9), the Clinical Global Impression Improvement (CGI-I) scale (Busner & Targum, 2007, Psychiatry (Edgmont) 4(7):28-37), and the Clinical Global Impression Severity Scale (CGI-I). It can be assessed using various scales and scores, such as the CGI-S (Clinical Global Indicator-Severity Severity) scale (Busner & Targum, 2007, Psychiatry (Edgmont). 4(7):28-37).Treatment of a subject with an AVPR1A agonist can include improving or slowing the worsening of one or more negative symptoms as measured by one or more of these scales or scores, or portions thereof.

[0056] In another aspect, the present disclosure provides a method for treating a subject suffering from neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease or amyotrophic lateral sclerosis (ALS), comprising administering an AVPR1A agonist to the subject in an amount effective for treating the subject.The treatment can include improving or slowing the progression of one or more negative symptoms of neurodegenerative diseases, such as antisociality, anhedonia, allopathic, flat affect, apathy, apathy, blunted affect, anergy, depression, low mood, and cognitive impairment.Negative symptoms and the changes in such symptoms can be evaluated by various scales and scores, such as those described in the previous paragraph.

[0057] In some embodiments, the present disclosure provides a method for treating a subject suffering from Parkinson's disease, comprising administering an AVPR1A agonist to the subject in an amount effective for treating the subject.The treatment can include improving or slowing the progression of one or more non-motor symptoms of Parkinson's disease.Non-motor symptoms of Parkinson's disease include sensory symptoms (e.g., numbness, restlessness, pain, chest discomfort, loss of smell), cognitive symptoms (e.g., mood swings, depression, anxiety, panic attacks, fatigue, confusion, slowed thinking), and autonomic symptoms (e.g., hot / cold sensation, bladder abnormalities, sweating, abdominal discomfort, constipation, salivation (drooling or excessive salivation), frequent and / or urgent urination, erectile dysfunction) (see, for example, Barone et al., 2009, Mov Disord.24(11):1641-9). Non-motor symptoms and changes in such symptoms can be measured using, for example, the Non-motor Symptoms Scale (NMSS) (Chaudhuri et al., 2007, Movement Disorders 22(13):1901-11), the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) non-motor symptom score (Goetz et al., International Parkinson's Disease and Movement Disorder Society, updated August 13, 2019; www.movementdisorders.org / MDS-Files1 / PDFs / MDS-UPDRS_English_FINAL.pdf), the Fatigue Severity Scale (FSS) score (Krupp et al., 1989, Arch Neurol. 46(10):1121-3), and the Beck's Depression Inventory II. BDI-II (Beck, Steer, & Brown, 1996), Beck Anxiety Inventory (BAI) scores (Beck et al., 1988, J Consult Clin Phychol.56(6):893-7), Montreal Cognitive Assessment (MoCA) score (Nasreddine et al., 2005, J Am Geriatr Soc. 53(4):695-9), score on the Cogstate test (cogstate.com), Clinical Global Impression-Improvement (CGI-I) total score or non-motor symptom score (Busner & Targum, 2007, Psychiatry (Edgmont). 4(7):28-37), Clinical Global Impression-Severity (CGI-S) total score or non-motor symptom score (Busner & Targum, 2007, Psychiatry (Edgmont). 4(7):28-37), and Parkinson's Disease Questionnaire-39 (PDQ-39) (Jenkinson et al., 1997, Age Ageing).26(5):353-7). Cogstate tests include computerized cognitive assessments such as the Behavioral Pattern Separation Object Test, the Continuous Paired Associate Learning Test, the Face Name Associative Memory Exam, the Groton Maze Learning Test, the Identification Test, the International Daily Symbol Substitution Tests (medicines or symbols), the International Shopping List Test, the One Back Test, the One Card Learning Test, the Sustained Attention Test, the Sustained Attention to Response Test, and the Two Back Test.

[0058] In some embodiments, the present disclosure provides a method for improving or slowing the progression of a cognitive deficit in a subject, or for improving cognition in a subject without a cognitive deficit, comprising administering to the subject an AVPR1A agonist in an amount effective to improve cognition or slow the progression of the cognitive deficit.

[0059] In another aspect, the disclosure provides a method for treating a subject suffering from a gastrointestinal disease or condition, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0060] In another aspect, the present disclosure provides a method for treating a subject suffering from irritable bowel syndrome, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0061] In another aspect, the disclosure provides a method for treating a subject suffering from inflammatory bowel disease, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0062] In another aspect, the present disclosure provides a method for treating a subject suffering from ulcerative colitis, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0063] In another aspect, the present disclosure provides a method for treating a subject suffering from Crohn's disease, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0064] In another aspect, the disclosure provides a method for treating a subject suffering from constipation, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0065] In another aspect, the disclosure provides a method for treating a subject suffering from pain, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0066] In another aspect, the disclosure provides a method for treating a subject suffering from visceral pain, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0067] In another aspect, the disclosure provides a method for treating a subject suffering from rheumatoid arthritis, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0068] In another aspect, the present disclosure provides a method for treating a subject suffering from a migraine, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0069] In another aspect, the present disclosure provides a method for treating a subject suffering from a headache, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0070] In another aspect, the disclosure provides a method for treating a subject suffering from substance abuse (e.g., a substance use disorder such as a drug use disorder, a polysubstance use disorder, an alcohol use disorder, a nicotine use disorder, or a tobacco use disorder), comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject. In some embodiments, the subject has a drug use disorder. In some embodiments, the subject has a polysubstance use disorder. In some embodiments, the subject has an alcohol use disorder. In some embodiments, the subject has a nicotine use disorder. In some embodiments, the subject has a tobacco use disorder.

[0071] In another aspect, the present disclosure provides a method for treating the subject suffering from drug addiction, comprising administering to the subject an AVPR1A agonist in an amount effective for treating the subject.Examples of drug addiction include opioid addiction, for example, addiction to morphine, heroin, oxycodone or fentanyl, cocaine addiction, and benzodiazepine addiction, for example, addiction to diazepam, alprazolam or clonazepam.

[0072] In another aspect, the present disclosure provides a method for treating a subject suffering from a seizure disorder, comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.In some embodiments, the seizure disorder is epilepsy.In some embodiments, the seizure disorder is orphan epilepsy (see, for example, Perucca et al., 2020, Lancet 19:544-556).

[0073] In another aspect, the present disclosure provides a method for treating a subject suffering from major depressive disorder, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0074] In another aspect, the present disclosure provides a method for treating a subject suffering from atypical depression, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0075] In another aspect, the present disclosure provides a method for treating a subject suffering from a major depressive episode (MDE) (e.g., atypical MDE), comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0076] In another aspect, the present disclosure provides a method for treating a subject suffering from depression in the presence of a neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease, or ALS), comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject. Depression in subjects with neurodegenerative diseases is typically resistant to traditional antidepressant treatment (Hussain et al., 2020, Cureus 12(11):e11613).

[0077] In another aspect, the present disclosure provides a method for treating a subject suffering from treatment-resistant depression, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0078] In another aspect, the present disclosure provides a method for treating a subject suffering from a cognitive disorder, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0079] In another aspect, the present disclosure provides a method for treating a subject suffering from Alzheimer's disease, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0080] In another aspect, the disclosure provides a method for treating a subject suffering from COVID-19-associated cognitive impairment and / or COVID-19-associated depression, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0081] In another aspect, the disclosure provides a method for treating a subject suffering from ADHD, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0082] In another aspect, the disclosure provides a method for treating a subject suffering from an autism spectrum disorder, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0083] In another aspect, the disclosure provides a method for treating a subject suffering from a pervasive developmental disorder, such as Asperger's syndrome or Rett's syndrome, comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0084] In another aspect, the disclosure provides a method for treating a subject suffering from a pervasive developmental disorder not otherwise specified, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0085] In another aspect, the present disclosure provides a method for treating a subject suffering from multiple sclerosis, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0086] In another aspect, the disclosure provides a method for treating a subject suffering from PTSD, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0087] In another aspect, the present disclosure provides a method for treating a subject suffering from a sleep disorder, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0088] In another aspect, the present disclosure provides a method for treating a subject suffering from insomnia, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0089] In another aspect, the present disclosure provides a method for treating a subject suffering from daytime fatigue, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0090] In another aspect, the present disclosure provides a method for treating a subject suffering from REM sleep behavior disorder, the method comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.

[0091] In another aspect, the present disclosure provides a method for improving sleep in a subject, the method comprising administering to the subject an AVPR1A agonist in an amount effective to improve sleep in the subject.

[0092] In another aspect, the present disclosure provides a method for treating a subject suffering from or at risk of a psychiatric disorder, comprising administering to the subject an AVPR1A agonist in an amount effective to treat the subject.In some embodiments, the psychiatric disorder is a mood disorder, an anxiety disorder, or a motivation-decreasing disorder.In some embodiments, the psychiatric disorder is depression, bipolar disorder, or adjustment disorder.In some embodiments, the psychiatric disorder is an anxiety disorder.In some embodiments, the psychiatric disorder is a motivation-decreasing disorder, such as apathy, apathy, or akinetic mutism.

[0093] In another aspect, the present disclosure provides a method for improving cognitive function in a subject, comprising administering to the subject an AVPR1A agonist in an amount effective to improve cognitive function. The subject may be a healthy subject, e.g., a subject not suffering from a condition described herein.

[0094] In another aspect, the present disclosure provides a method for improving mood in a subject, comprising administering to the subject an AVPR1A agonist in an amount effective to improve mood. The subject may be a healthy subject, e.g., a subject not suffering from a condition described herein.

[0095] In another aspect, the present disclosure provides a method for improving or slowing the deterioration of a subject's overall Patient Health Questionnaire 9 (PHQ-9) score, comprising administering to the subject an AVPR1A agonist in an amount effective to improve or slow the deterioration of the subject's overall PHQ-9 score. The subject may be a healthy subject, e.g., a subject not suffering from a condition described herein.

[0096] In another aspect, the disclosure provides a method for improving or delaying the deterioration of a subject's score on one or more of the PHQ-9 questions, such as PHQ-9 questions 1, 2, 3, or 6, comprising administering to the subject an AVPR1A agonist in an amount effective to improve or delay the deterioration of the subject's score on the PHQ-9 questions.

[0097] In another aspect, the present disclosure provides a method for improving or slowing the deterioration of one or more of a subject's CogState Groton Maze Test (GMLT), CogState Discrimination Test (IDN), or CogState 1 Card Test (OCL) results, comprising administering to the subject an AVPR1A agonist in an amount effective to improve or slow the deterioration of the subject's results on GMLT, IDN, and / or OCL. The subject may be a healthy subject, e.g., a subject not suffering from a condition described herein.

[0098] In another aspect, the present disclosure provides a method for improving or slowing the deterioration of at least one of alpha band power or gamma band power in an electroencephalogram (EEG) of a subject. The subject may be a healthy subject, e.g., a subject not suffering from a condition described herein.

[0099] In some embodiments of the methods described herein, the subject has elevated TNF-α levels, e.g., compared to a reference range obtained from a healthy subject. For example, in some embodiments, a subject with elevated TNF-α levels has a serum TNF-α level greater than 5.6 pg / ml, e.g., as measured by a sandwich immunoassay (e.g., Eurofins Viracor TNF-α Serum test; www.eurofins-viracor.com / clinical / test-menu / 1220-tnf-alpha-tnf-a-serum).

[0100] The subject of the methods described herein is preferably a mammal, such as a human or a household pet (e.g., a cat, a dog). The subject can be of any age, but is preferably an adult (e.g., a human subject aged 18 years or older, 25 years or older, 35 years or older, 45 years or older, 55 years or older, etc.). In some embodiments, the subject is elderly (e.g., a human subject aged 65 years or older, 70 years or older, 75 years or older, or 80 years or older).

[0101] AVPR1A agonists and pharmaceutical compositions containing them can be administered orally, topically, rectally, or parenterally, with oral administration being preferred. The method of administration can vary depending on the condition and age of the subject.

[0102] Suitable daily doses of AVPR1A agonists may range from 0.005 mg / kg to 500 mg / kg of body weight per day (e.g., 0.005 mg / kg to 100 mg / kg, 0.005 mg / kg to 30 mg / kg, 0.005 mg / kg to 1 mg / kg, 0.01 mg / kg to 30 mg / kg, 0.01 mg / kg to 3 mg / kg, 0.01 mg / kg to 1 mg / kg, 0.02 mg / kg to 5 mg / kg, 0.02 mg / kg to 2 mg / kg, 0.02 mg / kg to 1 mg / kg). Alternatively, the compound can be administered as a fixed dose ranging from 0.1 mg to 50 g per day (e.g., 0.1 mg to 10 g, 0.1 mg to 3 g, 0.1 mg to 100 mg, 0.1 mg to 1 mg, 0.3 mg to 3 g, 0.3 mg to 100 mg, 20 mg to 2 g, 20 mg to 1 g, 0.5 g to 2 g, 0.5 g to 1 g, or 1 g to 2 g). When a pharmaceutical composition is administered, an amount of the pharmaceutical composition containing an amount of AVPR1A agonist within one of the aforementioned ranges can be administered. The daily dose can be administered as a single or multiple doses.

[0103] AVPR1A agonists can be administered as sole therapy or in combination with one or more additional therapeutic agents, for example, one or more agents that are not AVPR1A agonists. [Example]

[0104] Example 1: Characterization of the LSSTQAQQSY (SEQ ID NO: 1) target To characterize the molecular target of LSSTQAQQSY (SEQ ID NO: 1), several screens were performed. Initial screens included screening of Trp channels (TRPA1, TRPV1), nutrient- and metabolite-sensing GPCRs (FFAR1, FFAR2, FFAR3, FFAR4, GPR119, CaS, GPR142, GPBAR1, and LPA5), and taste receptors; a genome-wide binding-based screen of all cell surface-expressed receptors (approximately 6K receptors); and a large-scale screen of 168 GPCRs for agonist or antagonist activity. These initial screens were negative or yielded irreproducible hits.

[0105] Next, we employed a more universal and sensitive GPCR screening strategy, which identified three potential targets: GNRHR, AVPR1A, and AVPR2. We then performed target identification and validation studies.

[0106] In the tail suspension test (TST) (see WO 2016 / 140277), the effects of LSSTQAQQSY (SEQ ID NO: 1) were found to be blocked by the AVPR1A / AVPR2 inhibitor conivaptan, suggesting that the primary target of LSSTQAQQSY (SEQ ID NO: 1) is either AVPR1A or AVPR2 (Figures 1-2). The effects of LSSTQAQQSY (SEQ ID NO: 1) were found not to be blocked by the AVPR2 inhibitor tolvaptan (Figure 3), suggesting that AVPR2 is not the primary target of this peptide. The effects of LSSTQAQQSY (SEQ ID NO: 1) were also found to be blocked by the AVPR1A / B inhibitor nerivaptan (Figure 4), indicating that the primary target of this peptide is AVPR1A.

[0107] The results of these studies are summarized in Table 1. [Table 1]

[0108] Example 2: LSSTQAQQSY (SEQ ID NO: 1) Brain Microdialysis Study A study was conducted to determine the CNS neurotransmitter responses elicited by oral administration of the peptide LSSTQAQQSY (SEQ ID NO: 1).

[0109] Male C57Bl / 6 mice were fitted with microdialysis probes in the prefrontal cortex (which regulates sensory processing, memory, and emotion) or striatum (required for behavioral reinforcement by natural rewards). Animals were orally administered a single 3 mg / kg dose of peptide or vehicle. Brain dialysate samples were collected before administration and every 30 minutes for 4 hours after administration. Concentrations of dopamine, norepinephrine, serotonin, histamine, glutamate, GABA, and glycine in the dialysate samples were determined by HPLC-MS.

[0110] The results are shown in Figures 5A to 5G and 6A to 6G.

[0111] Statistically significant changes in histamine and norepinephrine were observed in the prefrontal cortex, but no significant changes in other neurotransmitters were observed in the prefrontal cortex, and no significant changes in any neurotransmitters evaluated were observed in the striatum.

[0112] Example 3: Inflammation suppression by LSSTQAQQSY (SEQ ID NO: 1) Vagus nerve stimulation has been reported to suppress lipopolysaccharide (LPS)-induced increases in serum levels of the proinflammatory cytokine TNF-α (see, e.g., Tarnawski et al., 2018, Front. Immunol. 9:2648; Komegae et al., 2018, Brain Behav. Immun. 73:441-449). Because the peptide LSSTQAQQSY (SEQ ID NO: 1) is thought to act via the vagus nerve, we evaluated the peptide's ability to suppress TNF-α after LPS injection.

[0113] Mice were administered LPS i.p. at a dose of 10 μg / kg. 2.5 and 3.5 hours after LPS administration, the peptide LSSTQAQQSY (SEQ ID NO: 1) was administered po twice at 0.3 mg / kg, 3 mg / kg, or 10 mg / kg. Blood was collected 4 hours after LPS administration. Plasma levels of TNF-α were then measured by ELISA.

[0114] The results are shown in Figure 7. A trend towards TNF-α suppression was observed in animals administered the peptide after in vivo challenge with LPS, indicating the anti-inflammatory effect of this peptide.

[0115] Example 4: Improvement of mood and cognition in healthy subjects in a Phase 1a / 1b study A Phase 1a / 1b randomized, placebo-controlled crossover study was conducted using the peptide LSSTQAQQSY (SEQ ID NO: 1) in healthy subjects. The study population included men and women in good general health.

[0116] The single ascending dose (SAD) group included four cohorts receiving 60 mg / day (cohorts SAD1 and SAD2), 180 mg / day (cohort SAD3), or 540 mg / day (cohort SAD4) of peptide or placebo (see Figure 8A). The first multiple ascending dose (MAD) cohort (MAD cohort 1) included three groups receiving 60 mg / day (MAD1), 180 mg / day (MAD2), or 540 mg / day (MAD3) of peptide or placebo for 7 days. All doses were administered orally (see Figure 8B). The second MAD cohort (MAD cohort 1) used a crossover study design. One group of participants (n = 7) started with 540 mg of peptide once daily for 7 days, followed by 24 hours of sleep deprivation. Seven days after the end of dosing, this group was then switched to a placebo once daily for seven days, followed by another 24-hour sleep deprivation. They then crossed over to 540 mg of peptide once daily for seven days. The other group (n=7, one participant dropped out after initiation for personal reasons) used the reverse dosing regimen, with participants starting on a placebo and then crossing over to 540 mg of peptide once daily (see Figure 8C). Subjects were examined after 24 hours of sleep deprivation.

[0117] result safety Several members of each cohort experienced mild adverse effects, typically gastrointestinal upset or throat irritation. Vital signs, electrocardiogram (ECG) data, and physical examinations were normal for all study participants throughout the trial, except for two subjects in MAD Cohort 1 who were unable to undergo evaluation due to positive COVID tests and one participant in MAD Cohort 2 who left the study for personal reasons.

[0118] Patient Questionnaire-MAD Cohort 1 Results Approximately four hours after each placebo and peptide administration period, subjects in the MAD1 to MAD3 groups completed the Patient Health Questionnaire-9 (PHQ-9), a standard questionnaire for assessing depression severity. Each of the nine questions asked subjects how frequently they had experienced the following in the past two weeks: [Table 2-1] [Table 2-2]

[0119] Each question was answered on a scale of 0 to +3, with 0 being not at all, +1 being several days, +2 being more than half the time, and +3 being almost every day.

[0120] We assessed whether the peptides produced improvement over placebo on each question on the PHQ-9.

[0121] Preliminary data indicate that administration of the peptide resulted in improvements in measures of mood, depression, sleep, consciousness, and / or alertness in the MAD3 group (improvements in responses to PHQ-9 questions 1–3 and 6, along with the PHQ-9 total score, summarized in Figure 9 ).

[0122] CogState Subjects in the MAD1-MAD3 groups also underwent the following cognitive assessments (CogState Ltd., Melbourne, Victoria, Australia): 1) the Detection Test (DET), assessing psychomotor function; 2) the Groton Maze Learning Test (GMLT), assessing executive function; 3) the Identification Test (IDN), assessing attention; and 4) the One-Card Learning Test (OCL), assessing visual learning. The cognitive assessments were conducted essentially simultaneously with the administration of the PHQ-9 questionnaire to subjects. We qualitatively determined whether the peptides produced improvements over placebo in these four cognitive assessments.

[0123] Preliminary data indicate that the peptide had no significant effect on psychomotor function in healthy subjects (Figure 10). Preliminary data also show favorable trends in GMLT (Figure 11), IDN (Figure 12), and OCL (not shown) after 7 days of treatment.

[0124] Figure 13A shows the composite cognitive scores for the placebo and peptide-treated groups in MAD Cohort 2 (crossover study) on Day 1 (pre-dose) and Day 7 (4 hours post-dose). No statistically significant difference was observed between the cognitive scores of the placebo and peptide-treated groups on Day 1. (Five of 13 peptide-treated subjects had better scores than the placebo.) On Day 7, 12 of 13 peptide-treated subjects had improved composite cognitive scores (p<0.01).

[0125] Figure 13B shows radar plots for four Cogstate tests: the Detection Test (DET), the Groton Maze Learning Test (GMLT), the Discrimination Test (IDN), and the One-Card Learning Test (OCL) for 13 subjects in MAD Cohort 2. Figure I shows test scores for the four tests in placebo-treated subjects (the leftmost bar in each pair of bars for each test) and peptide-treated subjects (the rightmost bar in each pair of bars for each test). Lower scores indicate better cognition. Twelve of the 13 subjects improved compared to placebo on at least one of the four tests. Test improvements were most consistent in the Groton Maze Learning test (n = 9 / 13; p < 0.03).

[0126] Overall, these results confirmed that 7 days of peptide administration improved cognitive scores in healthy volunteers.

[0127] In conclusion, data from this study show that treatment with the peptide improved executive function, attention, and visual learning in subjects.

[0128] Alpha and Gamma Electroencephalogram (EEG) Bands - MAD Cohort 1 Quantitative EEG (qEEG) metrics can be used as biomarkers for Alzheimer's disease. In Alzheimer's disease, Parkinson's disease, and mild cognitive impairment (MCI), EEG changes include increased theta power compared to age-matched healthy controls and decreased alpha power compared to age-matched healthy controls. (See, for example, Meghdadi AH, et al., "Resting state EEG biomarkers of cognitive decline associated with Alzheimer's disease and mild cognitive impairment," PloS One. 2021 Feb 5;16(2).)

[0129] The different bands observed in the EEG are generally associated with different states of mental activity, as summarized in the table below. [Table 3]

[0130] Across all MAD groups, quantitative EEG (qEEG) was recorded for some subjects immediately before the final dose (day 7) and approximately 1, 2, 4, 8, and 12 hours after the final dose. Power in each band was recorded immediately before the first dose (day 10 was defined as baseline (100%), against which post-dose EEG band power was normalized).

[0131] Preliminary data from the MAD1 group, in which each dose contained 60 mg of peptide, showed a significant increase in power in the alpha band, from approximately 80% of baseline before the last dose to approximately 150% of baseline just 1 hour after the last dose. Alpha band power ranged from approximately 120% to approximately 200% by approximately 12 hours after the last dose. Gamma band power similarly increased from approximately 100-110% of baseline before the last dose to approximately 140% of baseline 1 hour after the last dose, remaining above approximately 125% of baseline for 8 hours.

[0132] Preliminary data from the MAD2 group, in which each dose contained 180 mg of peptide, also showed significant increases in power in the alpha and gamma bands. Alpha band power increased from approximately 110% of baseline before the last dose to approximately 150% of baseline 2 hours after the last dose and remained above 110% of baseline until approximately 12 hours after the last dose. Gamma band power increased from approximately 100-110% of baseline before the last dose to approximately 125% of baseline 1 hour after the last dose and remained above 150% of baseline until approximately 12 hours after the last dose.

[0133] Preliminary data from the MAD3 group, where each dose contained 540 mg of peptide, showed a decrease in alpha band power from approximately 100% of baseline before the last dose to approximately 70-80% of baseline 1-12 hours after the last dose.

[0134]

[0135] In summary, preliminary data from this study indicate that treatment with the peptide at doses of 60 mg / day or 180 mg / day increased power in the alpha and gamma EEG bands, which is indicative of a state of relaxed awareness and focused concentration.

[0136] Figure 14 illustrates theta and alpha power for the MAD groups at different dose levels, and Figure 15 illustrates alpha power levels in the eyes-open and eyes-closed states for the MAD groups at different dose levels.

[0137] Sleep quality assessment Sleep quality was also assessed in the MAD cohort using the insomnia severity index (ISI). The ISI is a multidimensional, 7-item self-report scale assessing the severity of sleep quality problems (0 = no problems to 4 = severe problems). In MAD cohort 1, 7 days of peptide administration resulted in a dose-dependent improvement in sleep quality, as evidenced by a decrease in ISI (see Figure 16A). Improvements in sleep quality were observed after 7 days of 540 mg peptide administration in both MAD cohort 1 (Figure 16B) and the crossover study (MAD cohort 2) (Figure 16C).

[0138] The alpha slow wave index (ASI; alpha / (delta + theta)) in the frontal cortex is widely used as an objective measure of vigilance. An increase in ASI indicates vigilance, whereas a decrease in ASI indicates sleepiness or a lack of selective focus. As shown in Figure 17A, peptide-treated subjects exhibited a dose-dependent increase in ASI. Improvements in reported sleep quality correlated with ASI changes in the frontal cortex (Fz eyes closed). See Figure 17B.

[0139] These results suggest that peptide LSSTQAQQSY (SEQ ID NO: 1) modulates alpha power in both eyes-open and eyes-closed states. In contrast to reduced alpha power in Alzheimer's disease, Parkinson's disease, and cognitive impairment, peptide LSSTQAQQSY (SEQ ID NO: 1) increases alpha power, which correlates with improved cognition, mood, and sleepiness.

[0140] Example 5: Pharmacological studies with felypressin The effects of orally administered felypressin, a selective AVPR1A agonist, were evaluated for antidepressant activity in the mouse tail suspension test. Felypressin at 0.03 mg / kg, 0.1 mg / kg, and 0.3 mg / kg were compared with 0.3 mg / kg of the peptide LSSTQAQQSY (SEQ ID NO: 1) (n = 6 per group). The effects of orally administered felypressin (0.1 mg / kg) were also compared with orally administered felypressin (0.1 mg / kg) plus the AVPR1A / AVPR2 inhibitor conivaptan (3 mg / kg) (n = 7 per group).

[0141] The results are shown in Figures 18 and 19. As shown in Figures 18 and 19, AVPR1A activation induced antidepressant effects. The AVPR1A / AVPR2 inhibitor conivaptan blocked the activity of felypressin in the tail suspension test.

[0142] Example 6: Pharmacological studies with desmopressin The effects of orally administered desmopressin, which exhibits greater selectivity for AVPR2 over AVPR1A, were evaluated for antidepressant activity in the mouse tail suspension test. In the first study, desmopressin at 0.03 mg / kg, 0.1 mg / kg, and 0.3 mg / kg were compared with felypressin at 0.1 mg / kg (n = 6 per group). In the first study, desmopressin at 0.1 mg / kg, 0.3 mg / kg, and 1.0 mg / kg was compared with felypressin at 0.1 mg / kg (n = 6 per group).

[0143] The results are shown in Figures 20 and 21. As shown in Figures 20 and 21, desmopressin showed a smaller effect than felypressin.

[0144] Example 7: Histological analysis of peptide LSSTQAQQSY (SEQ ID NO: 1) in the upper gastrointestinal tract To understand the mechanism of action of the peptide LSSTQAQQSY (SEQ ID NO: 1), tissue sections from mouse gastrointestinal tissue were stained with the fluorescently labeled peptide and with cell-specific markers, using different colors for each stain. Peptide binding did not overlap with general enterocyte marker staining, but peptide binding did overlap with enteroendocrine sensory cell markers (data not shown).

[0145] These results indicate that the peptide interacts with sensory cells in the upper gastrointestinal tract.

[0146] Example 8: Dose-dependence and effects of repeated administration of peptide LSSTQAQQSY (SEQ ID NO: 1) Oral administration of the peptide LSSTQAQQSY (SEQ ID NO: 1) enhances stress resilience in mice, as evidenced by the tail suspension test (TST). This example examines whether this effect is dose-dependent and whether repeated administration affects efficacy.

[0147] Mice were administered vehicle or 0.03 mg / kg, 0.3 mg / kg, 3 mg / kg, or 10 mg / kg of the peptide and subjected to TST. A decrease in immobility time (indicating stress resilience) was observed at 3 mg / kg and 10 mg / kg, with a greater difference between the vehicle-treated and peptide-treated groups at the 10 mg / kg dose (see Figure 22).

[0148] In another series of experiments, mice were repeatedly administered the peptide and subjected to the TST. Repeated administration of the peptide at 2-hour intervals (Figure 23A) and daily for 5 days (Figure 23B) increased efficacy.

[0149] Citing References While various specific embodiments have been illustrated and described, it will be understood that various changes can be made without departing from the spirit and scope of the disclosure.

[0150] Numbered Embodiments The present disclosure is illustrated by the numbered embodiments set forth below. 1. (a) A method for treating a subject suffering from or at risk of (i) a disease or disorder of the nervous system or (ii) an inflammatory disease or disorder, or (b) a method for improving sleep in a subject, or (c) a method for improving cognition in a subject, comprising administering to the subject a therapeutically effective amount of an arginine vasopressin receptor 1A (AVPR1A) agonist, wherein the AVPR1 agonist may be an AVPR1A agonist described herein. 2. The method of embodiment 1, wherein the AVPR1A agonist has greater selectivity for AVPR1A over AVPR1B. 3. The method of embodiment 1 or embodiment 2, wherein the AVPR1A agonist has greater selectivity for AVPR1A over AVPR2. 4. The method of embodiment 1, wherein the AVPR1A agonist is vasopressin, a vasopressin analog, or a pharmaceutically acceptable salt thereof. 5. The method of embodiment 1 or embodiment 4, wherein the AVPR1A agonist is vasopressin or a pharmaceutically acceptable salt thereof. 6. The method of embodiment 1 or embodiment 4, wherein the AVPR1A agonist is a vasopressin analogue or a pharmaceutically acceptable salt thereof. 7. Embodiment 6, in which the vasopressin analog has greater selectivity for AVPR1A over AVPR1B. 8. The method of embodiment 6 or embodiment 7, wherein the AVPR1A agonist has greater selectivity for AVPR1A over AVPR2. 9. The method of embodiment 1 or embodiment 6, wherein the AVPR1A agonist is desmopressin, felypressin, ornipressin, selepressin, terlipressin, lypressin, F180, [deamino-Cys(1)]arginine vasopressin (dAVP), or a pharmaceutically acceptable salt thereof. 10. The method of embodiment 9, wherein the AVPR1A agonist is desmopressin or a pharmaceutically acceptable salt thereof. 11. The method of embodiment 9, wherein the AVPR1A agonist is felypressin or a pharmaceutically acceptable salt thereof. 12. The method of embodiment 9, wherein the AVPR1A agonist is ornipressin or a pharmaceutically acceptable salt thereof. 13. The method of embodiment 9, wherein the AVPR1A agonist is selepressin or a pharmaceutically acceptable salt thereof. 14. The method of embodiment 9, wherein the AVPR1A agonist is terlipressin or a pharmaceutically acceptable salt thereof. 15. The method of embodiment 9, wherein the AVPR1A agonist is lypressin or a pharmaceutically acceptable salt thereof. 16. The method of embodiment 9, wherein the AVPR1A agonist is F180 or a pharmaceutically acceptable salt thereof. 17. The method of embodiment 9, wherein the AVPR1A agonist is [deamino-Cys(1)]arginine vasopressin (dAVP) or a pharmaceutically acceptable salt thereof. 18. The method of any one of embodiments 1-17, wherein the subject is suffering from or at risk of a disease or disorder of the nervous system. 19. The method of embodiment 18, wherein the subject is suffering from or at risk of a disease or disorder of the central nervous system. 20. The method of any one of embodiments 1-17, wherein the subject is suffering from or at risk of an inflammatory disease or disorder. 21. The method according to any one of embodiments 1-17, wherein the method is a method for improving sleep in a subject. 22. The method of any one of embodiments 1-17, wherein the subject has or is at risk for an inflammatory disease or disorder, schizophrenia or psychosis, a neurodegenerative disease, a gastrointestinal disease or disorder, pain, rheumatoid arthritis, migraine, headache, substance abuse, drug addiction, a seizure disorder, major depressive disorder, atypical depression, a major depressive episode (MDE), treatment-resistant depression, depression in the presence of a neurodegenerative disease, cognitive impairment, COVID-19 associated cognitive impairment and / or COVID-19 associated depression, ADHD, autism spectrum disorder, pervasive developmental disorder, atypical autism, multiple sclerosis, PTSD, or a sleep disorder. 23. The method of any one of embodiments 1-17, wherein the subject suffers from or is at risk of schizophrenia or psychosis. 24. The method of embodiment 23, wherein the subject has or is at risk of having schizophrenia. 25. The method of any one of embodiments 23-24, wherein the subject exhibits psychotic behavior. 26. The method of any one of embodiments 24-26, wherein treatment comprises ameliorating or slowing the progression of one or more negative symptoms of schizophrenia or psychosis. 27. The method of any one of embodiments 1-26, wherein treating comprises ameliorating or slowing the progression of one or more negative symptoms of a disease or disorder of the central nervous system. 28. The method of embodiment 26 or embodiment 27, wherein the one or more negative symptoms comprise antisociality, anhedonia, allogia, flat affect, apathy, amotivation, blunted affect, anergia, apathy, depression, low mood, cognitive impairment, or a combination thereof. 29. The method of embodiment 28, wherein the one or more negative symptoms include antisocial behavior. 30. The method of embodiment 28 or embodiment 29, wherein the one or more negative symptoms comprises anhedonia. 31. The method of any one of embodiments 28-30, wherein one or more negative symptoms include allogeneic. 32. The method of any one of embodiments 28-31, wherein the one or more negative symptoms comprises flat affect. 33. The method of any one of embodiments 28-32, wherein the one or more negative symptoms comprises apathy. 34. The method of any one of embodiments 28-33, wherein the one or more negative symptoms include loss of motivation. 35. The method of any one of embodiments 28-34, wherein the one or more negative symptoms comprises blunted affect. 36. The method of any one of embodiments 28-35, wherein the one or more negative symptoms comprises anergy. 37. The method of any one of embodiments 28-36, wherein the one or more negative symptoms comprises apathy. 38. The method of any one of embodiments 28-37, wherein the one or more negative symptoms comprises depression. 39. The method of any one of embodiments 28-38, wherein the one or more negative symptoms comprises depressed mood. 40. The method of any one of embodiments 28-39, wherein the one or more negative symptoms comprises cognitive impairment. 41. The method of any one of embodiments 1-40, wherein treatment comprises improving or slowing the progression of a cognitive deficit in the subject, wherein the cognitive deficit may comprise a deficit in verbal working memory, spatial working memory, verbal fluency, verbal learning, or a combination thereof. 42. The method of any one of embodiments 1-41, wherein the subject is suffering from a neurodegenerative disease. 43. The method of any one of embodiments 1-42, wherein the subject is suffering from Parkinson's disease. 44. The method of embodiment 43, wherein treatment comprises improving or slowing the progression of one or more non-motor symptoms of Parkinson's disease in the subject. 45. The method of embodiment 44, wherein the one or more non-motor symptoms include sensory symptoms, cognitive symptoms, autonomic symptoms, or a combination thereof. 46. ​​The method of embodiment 45, wherein the one or more non-motor symptoms include one or more sensory symptoms. 47. The method of embodiment 46, wherein the one or more sensory symptoms comprise numbness, restlessness, pain, chest discomfort, loss of smell, or a combination thereof. 48. The method of any one of embodiments 44-47, wherein the one or more non-motor symptoms include one or more cognitive symptoms. 49. The method of embodiment 48, wherein the one or more cognitive symptoms comprise mood swings, depression, anxiety, panic attacks, fatigue, confusion, slowed thinking, or a combination thereof. 50. The method of any one of embodiments 45-49, wherein the one or more non-motor symptoms include one or more autonomic symptoms. 51. The method of embodiment 50, wherein the one or more autonomic symptoms comprise hot / cold sensation, bladder abnormalities, sweating, abdominal discomfort, constipation, salivation, urination frequency and / or urgency, erectile dysfunction, or a combination thereof. 52. The method of any one of embodiments 44-51, wherein the one or more non-motor symptoms comprise cognitive deficits and / or impairment, depression, anxiety, fatigue, apathy, or a combination thereof. 53. The method of any one of embodiments 1-17, wherein the subject is suffering from a gastrointestinal disease or disorder. 54. The method of any one of embodiments 1-17, wherein the subject is suffering from irritable bowel syndrome. 55. The method of any one of embodiments 1-17, wherein the subject is suffering from inflammatory bowel disease. 56. The method of any one of embodiments 1-17, wherein the subject is suffering from Crohn's disease. 57. The method of any one of embodiments 1-17, wherein the subject is suffering from ulcerative colitis. 58. The method of any one of embodiments 1-17, wherein the subject is suffering from pain (e.g., visceral pain). 59. The method of any one of embodiments 1-17, wherein the subject suffers from rheumatoid arthritis. 60. The method of any one of embodiments 1-17, wherein the subject is suffering from migraine. 61. The method of any one of embodiments 1-17, wherein the subject is suffering from a headache. 62. The method of any one of embodiments 1-17, wherein the subject is suffering from substance abuse. 63. The method of any one of embodiments 1-17, wherein the subject is suffering from drug addiction. 64. The method of any one of embodiments 1-17, wherein the subject suffers from a seizure disorder. 65. The method of embodiment 64, wherein the seizure disorder is epilepsy. 66. The method of embodiment 65, wherein the epilepsy is a rare epilepsy. 67. The method of any one of embodiments 1-17, wherein the subject suffers from major depressive disorder. 68. The method of any one of embodiments 1-17, wherein the subject suffers from atypical depression. 69. The method of any one of embodiments 1-17, wherein the subject is suffering from a major depressive episode (MDE) (e.g., atypical MDE). 70. The method of any one of embodiments 1-17, wherein the subject suffers from treatment-resistant depression. 71. The method of any one of embodiments 1-17, wherein the subject is suffering from depression in the presence of a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease). 72. The method of any one of embodiments 1-17, wherein the subject suffers from a cognitive disorder. 73. The method of embodiment 72, wherein the cognitive impairment is mild cognitive impairment. 74. The method of any one of embodiments 1-17, wherein the subject is suffering from COVID-19 associated cognitive impairment and / or COVID-19 associated depression. 75. The method of any one of embodiments 1-17, wherein the subject is suffering from Alzheimer's disease. 76. The method of any one of embodiments 1-17, wherein the subject suffers from ADHD. 77. The method of any one of embodiments 1-17, wherein the subject suffers from an autism spectrum disorder. 78. The method of any one of embodiments 1-17, wherein the subject suffers from a pervasive developmental disorder, and the pervasive developmental disorder may be Asperger's syndrome or Rett's syndrome. 79. The method of any one of embodiments 1-17, wherein the subject suffers from atypical autism. 80. The method of any one of embodiments 1-17, wherein the subject is suffering from multiple sclerosis. 81. The method of any one of embodiments 1-17, wherein the subject suffers from PTSD. 82. The method of any one of embodiments 1-17, wherein the subject suffers from a sleep disorder. 83. The method of any one of embodiments 1-17, wherein the subject suffers from insomnia. 84. The method of any one of embodiments 1-17, wherein the subject suffers from daytime fatigue. 85. The method of any one of embodiments 1-17, wherein the subject suffers from REM sleep behavior disorder. 86. The method of any one of embodiments 1-17, wherein treatment comprises improving sleep in the subject. 87. The method of any one of embodiments 1-17, wherein the subject suffers from or is at risk of a psychiatric disorder. 88. The method of embodiment 87, wherein the psychiatric disorder is a mood disorder, an anxiety disorder, or a reduced motivation disorder. 89. The method of embodiment 88, wherein the psychiatric disorder is a mood disorder. 90. The method of embodiment 89, wherein the mood disorder comprises depression, bipolar disorder, or adjustment disorder. 91. The method of any one of embodiments 87-90, wherein the psychiatric disorder comprises depression. 92. The method of any one of embodiments 87-90, wherein the psychiatric disorder comprises bipolar disorder. 93. The method of any one of embodiments 87-90, wherein the psychiatric disorder comprises an adjustment disorder. 94. The method of embodiment 88, wherein the psychiatric disorder is an anxiety disorder. 95. The method of embodiment 88, wherein the psychiatric disorder is reduced motivation disorder. 96. The method of embodiment 95, wherein the reduced motivation disorder comprises apathy, apathy, or akinetic mutism. 97. The method of embodiment 96, wherein the reduced motivation disorder comprises apathy. 98. The method of embodiment 96, wherein the motivation-reducing disorder comprises amotivation. 99. The method of embodiment 96, wherein the reduced motivation disorder comprises akinetic mutism. 100. The method of any one of embodiments 1-99, wherein the AVPR1A agonist is administered as a monotherapy. 101. The method according to any one of embodiments 1-100, wherein the AVPR1A agonist is administered orally. 102. The method of any one of embodiments 1-101, wherein the subject has elevated TNF-α levels. 103. An AVPR1A agonist for use in a method according to any one of embodiments 1 to 102. 104. Use of an AVPR1A agonist in the manufacture of a medicament for treating any disease or disorder according to any one of embodiments 1-102.

[0151] 1. Incorporation by Reference All publications, patents, patent applications, and other documents cited in this application are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, and other document was individually indicated to be incorporated by reference for all purposes. In the event of any inconsistency between the teaching of one or more of the references incorporated herein and the present disclosure, the teaching of the present disclosure is intended.

Claims

1. (a) A method of treating a subject suffering from or at risk of (i) a disease or disorder of the nervous system or (ii) an inflammatory disease or disorder, or (b) a method of improving sleep in a subject, or (c) a method of improving cognition in a subject, comprising administering to the subject a therapeutically effective amount of an arginine vasopressin receptor 1A (AVPR1A) agonist, wherein the AVPR1 agonist may be an AVPR1A agonist described herein.

2. (a) A method of treating a subject suffering from or at risk of (i) a disease or disorder of the nervous system or (ii) an inflammatory disease or disorder, or (b) a method of improving sleep in a subject, or (c) a method of improving cognition in a subject, comprising administering to the subject a therapeutically effective amount of an agent comprising means for agonizing arginine vasopressin receptor 1A (AVPR1A).

3. 3. The method of claim 2, wherein the means for activating comprises an AVPR1A agonist.

4. 4. The method of claim 1 or claim 3, wherein the AVPR1A agonist is vasopressin, a vasopressin analog, or a pharmaceutically acceptable salt thereof.

5. 5. The method of claim 1, claim 3, or claim 4, wherein the AVPR1A agonist is vasopressin or a pharmaceutically acceptable salt thereof.

6. 5. The method of claim 1, claim 3, or claim 4, wherein the AVPR1A agonist is a vasopressin analog or a pharmaceutically acceptable salt thereof.

7. 10. The method of claim 1 or claim 6, wherein the AVPR1A agonist is felypressin, desmopressin, ornipressin, selepressin, terlipressin, lypressin, F180, [deamino-Cys(1)]arginine vasopressin (dAVP), or a pharmaceutically acceptable salt thereof.

8. The method of any one of claims 1 to 7, wherein the subject is suffering from or at risk of a disease or disorder of the nervous system.

9. 9. The method of claim 8, wherein the subject is suffering from or at risk for a disease or disorder of the central nervous system.

10. The method of any one of claims 1 to 7, wherein the subject is suffering from or at risk of an inflammatory disease or disorder.

11. The method of any one of claims 1 to 7, which is a method for improving sleep in a subject.

12. 8. The method of any one of claims 1 to 7, wherein the subject is suffering from or at risk of an inflammatory disease or disorder, schizophrenia or psychosis, a neurodegenerative disease, a gastrointestinal disease or disorder, pain, rheumatoid arthritis, migraine, headache, substance abuse, drug addiction, a seizure disorder, major depressive disorder, atypical depression, a major depressive episode (MDE), treatment-resistant depression, depression in the presence of a neurodegenerative disease, cognitive impairment, COVID-19 associated cognitive impairment and / or COVID-19 associated depression, ADHD, autism spectrum disorder, pervasive developmental disorder, atypical autism, multiple sclerosis, PTSD, or a sleep disorder.

13. The method of any one of claims 1 to 7, wherein the subject suffers from or is at risk of schizophrenia or psychosis.

14. 14. The method of claim 13, wherein the subject has or is at risk for schizophrenia.

15. 15. The method of claim 13 or claim 14, wherein the subject exhibits psychotic behavior.

16. 17. The method of any one of claims 14 to 16, wherein said treatment comprises ameliorating or slowing the progression of one or more negative symptoms of schizophrenia or psychosis.

17. 18. The method of any one of claims 1 to 17, wherein said treatment comprises ameliorating or slowing the progression of one or more negative symptoms of a disease or disorder of the central nervous system.

18. 18. The method of claim 16 or claim 17, wherein the one or more negative symptoms comprise antisociality, anhedonia, allogia, flat affect, apathy, amotivation, blunted affect, anergy, apathy, depression, low mood, cognitive impairment, or a combination thereof.

19. 20. The method of claim 18, wherein the one or more negative symptoms include antisocial behavior.

20. 20. The method of claim 18 or claim 19, wherein the one or more negative symptoms comprises anhedonia.

21. 21. The method of any one of claims 18 to 20, wherein the one or more negative symptoms comprise allogies.

22. 22. The method of any one of claims 18 to 21, wherein the one or more negative symptoms comprises flat affect.

23. 23. The method of any one of claims 18 to 22, wherein the one or more negative symptoms comprises apathy.

24. 24. The method of any one of claims 18 to 23, wherein the one or more negative symptoms comprises loss of motivation.

25. 25. The method of any one of claims 18 to 24, wherein the one or more negative symptoms comprises blunted affect.

26. 26. The method of any one of claims 18 to 25, wherein the one or more negative symptoms comprises anergy.

27. 27. The method of any one of claims 18 to 26, wherein the one or more negative symptoms comprises apathy.

28. 28. The method of any one of claims 18 to 27, wherein the one or more negative symptoms comprises depression.

29. 29. The method of any one of claims 18 to 28, wherein the one or more negative symptoms comprises depressed mood.

30. 30. The method of any one of claims 18 to 29, wherein the one or more negative symptoms comprises cognitive impairment.

31. 31. The method of any one of claims 1-30, wherein said treatment comprises improving or slowing the progression of a cognitive deficit in said subject, wherein said cognitive deficit may comprise a deficit in verbal working memory, spatial working memory, verbal fluency, verbal learning, or a combination thereof.

32. The method of any one of claims 1 to 31, wherein the subject is suffering from a neurodegenerative disease.

33. The method of any one of claims 1 to 32, wherein the subject is suffering from Parkinson's disease.

34. 34. The method of claim 33, wherein the treatment comprises improving or slowing the progression of one or more non-motor symptoms of Parkinson's disease in the subject.

35. 35. The method of claim 34, wherein the one or more non-motor symptoms comprise a sensory symptom, a cognitive symptom, an autonomic symptom, or a combination thereof.

36. 36. The method of claim 35, wherein the one or more non-motor symptoms include one or more sensory symptoms.

37. 37. The method of claim 36, wherein the one or more sensory symptoms comprise numbness, restlessness, pain, chest discomfort, loss of smell, or a combination thereof.

38. 38. The method of any one of claims 34 to 37, wherein the one or more non-motor symptoms include one or more cognitive symptoms.

39. 39. The method of claim 38, wherein the one or more cognitive symptoms comprise mood swings, depression, anxiety, panic attacks, fatigue, confusion, slowed thinking, or a combination thereof.

40. 40. The method of any one of claims 35 to 39, wherein the one or more non-motor symptoms include one or more autonomic symptoms.

41. 41. The method of claim 40, wherein the one or more autonomic symptoms comprise hot / cold sensations, bladder abnormalities, sweating, abdominal discomfort, constipation, salivation, urination frequency and / or urgency, erectile dysfunction, or a combination thereof.

42. 42. The method of any one of claims 34 to 41, wherein the one or more non-motor symptoms comprise cognitive deficits and / or impairment, depression, anxiety, fatigue, apathy, or a combination thereof.

43. The method of any one of claims 1 to 7, wherein the subject is suffering from a gastrointestinal disease or disorder.

44. The method of any one of claims 1 to 7, wherein the subject suffers from irritable bowel syndrome.

45. The method of any one of claims 1 to 7, wherein the subject is suffering from inflammatory bowel disease.

46. The method of any one of claims 1 to 7, wherein the subject is suffering from Crohn's disease.

47. The method of any one of claims 1 to 7, wherein the subject is suffering from ulcerative colitis.

48. The method of any one of claims 1 to 7, wherein the subject is suffering from pain (e.g., visceral pain).

49. The method of any one of claims 1 to 7, wherein the subject is suffering from rheumatoid arthritis.

50. The method of any one of claims 1 to 7, wherein the subject is suffering from migraine.

51. The method of any one of claims 1 to 7, wherein the subject is suffering from a headache.

52. The method of any one of claims 1 to 7, wherein the subject is suffering from substance abuse.

53. The method of any one of claims 1 to 7, wherein the subject is suffering from drug addiction.

54. The method of any one of claims 1 to 7, wherein the subject suffers from a seizure disorder.

55. 55. The method of claim 54, wherein the seizure disorder is epilepsy.

56. 56. The method of claim 55, wherein the epilepsy is a rare epilepsy.

57. The method of any one of claims 1 to 7, wherein the subject is suffering from major depressive disorder.

58. The method of any one of claims 1 to 7, wherein the subject is suffering from atypical depression.

59. The method of any one of claims 1 to 7, wherein the subject is suffering from a major depressive episode (MDE) (e.g., atypical MDE).

60. The method of any one of claims 1 to 7, wherein the subject suffers from treatment-resistant depression.

61. The method of any one of claims 1 to 7, wherein the subject is suffering from depression in the presence of a neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease).

62. The method of any one of claims 1 to 7, wherein the subject suffers from a cognitive disorder.

63. 63. The method of claim 62, wherein the cognitive impairment is mild cognitive impairment.

64. 8. The method of any one of claims 1 to 7, wherein the subject is suffering from COVID-19 associated cognitive impairment and / or COVID-19 associated depression.

65. The method of any one of claims 1 to 7, wherein the subject is suffering from Alzheimer's disease.

66. The method of any one of claims 1 to 7, wherein the subject is suffering from ADHD.

67. The method of any one of claims 1 to 7, wherein the subject suffers from an autism spectrum disorder.

68. 8. The method of any one of claims 1 to 7, wherein the subject suffers from a pervasive developmental disorder, and the pervasive developmental disorder may be Asperger's syndrome or Rett's syndrome.

69. The method of any one of claims 1 to 7, wherein the subject suffers from atypical autism.

70. The method of any one of claims 1 to 7, wherein the subject is suffering from multiple sclerosis.

71. The method of any one of claims 1 to 7, wherein the subject is suffering from PTSD.

72. The method of any one of claims 1 to 7, wherein the subject suffers from a sleep disorder.

73. The method of any one of claims 1 to 7, wherein the subject suffers from insomnia.

74. The method of any one of claims 1 to 7, wherein the subject suffers from daytime fatigue.

75. The method of any one of claims 1 to 7, wherein the subject suffers from REM sleep behavior disorder.

76. 8. The method of any one of claims 1 to 7, wherein the treatment comprises improving sleep in the subject.

77. The method of any one of claims 1 to 7, wherein the subject suffers from or is at risk of a psychiatric disorder.

78. 78. The method of claim 77, wherein the psychiatric disorder is a mood disorder, an anxiety disorder, or a reduced motivation disorder.

79. 79. The method of claim 78, wherein the psychiatric disorder is a mood disorder.

80. 80. The method of claim 79, wherein the mood disorder comprises depression, bipolar disorder, or adjustment disorder.

81. 81. The method of any one of claims 77 to 80, wherein the psychiatric disorder comprises depression.

82. 81. The method of any one of claims 77 to 80, wherein the psychiatric disorder comprises bipolar disorder.

83. 81. The method of any one of claims 77 to 80, wherein the psychiatric disorder comprises an adjustment disorder.

84. 79. The method of claim 78, wherein the psychiatric disorder is an anxiety disorder.

85. 79. The method of claim 78, wherein the psychiatric disorder is reduced motivation disorder.

86. 86. The method of claim 85, wherein the reduced motivation disorder comprises apathy, aactivity, or akinetic mutism.

87. 87. The method of claim 86, wherein the reduced motivation disorder comprises apathy.

88. 87. The method of claim 86, wherein the reduced motivation disorder comprises amotivation.

89. 87. The method of claim 86, wherein the reduced motivation disorder comprises akinetic mutism.

90. 90. The method of any one of claims 1 to 89, wherein the AVPR1A agonist is administered as a monotherapy.

91. 91. The method of any one of claims 1 to 90, wherein the AVPR1A agonist is administered orally.

92. 92. The method of any one of claims 1 to 91, wherein the subject has elevated TNF-α levels.

93. A method for treating a subject suffering from or at risk of Alzheimer's disease or Parkinson's disease, comprising administering to the subject a therapeutically effective amount of a vasopressin analog or a pharmaceutically acceptable salt thereof.

94. 1. A method of improving cognition in a subject, comprising administering to said subject a therapeutically effective amount of a vasopressin analogue or a pharmaceutically acceptable salt thereof.

95. 1. A method for improving sleep in a subject, comprising administering to the subject a therapeutically effective amount of a vasopressin analog or a pharmaceutically acceptable salt thereof.

96. A method for treating a subject suffering from or at risk of depression, comprising administering to the subject a therapeutically effective amount of a vasopressin analogue or a pharmaceutically acceptable salt thereof.

97. 97. The method of any one of claims 93 to 96, wherein the subject is a mammal.

98. 98. The method of claim 97, wherein the subject is a human.

99. 99. The method of any one of claims 93 to 98, wherein the vasopressin analogue is felypressin or desmopressin.

100. 100. The method of any one of claims 1 to 99, comprising administering the AVPR1A agonist or AVPR1A agent multiple times.

101. 101. An AVPR1A agonist for use in a method according to any one of claims 1 to 100.

102. Use of an AVPR1A agonist in the manufacture of a medicament for treating any of the diseases or disorders described herein.

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