# US 12,178,838 B2 · Synthetic neuromodulatory peptides

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- Number: US 12,178,838 B2
- Document ID: US12178838B2
- Status: Granted
- Kind: B2
- Application number: 17/437,331
- Filed: 2020-03-13
- Published: 2022-06-09
- Granted: 2024-12-31
- Earliest claimed: 2019-03-14
- Assignees: Lactocore, Inc.
- Applicants: Lactocore, Inc.
- Inventors: Anton Malyshev; Igor Doronin; Gennady Babkin; Askar Kuchumov
- Web page: https://patentgrep.com/patent/US12178838B2

## CPC

- A61K 38/07: Tetrapeptides
- C07K 5/1016: {and aromatic or cycloaliphatic}
- A61K 9/0043: {Nose}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/22: Anxiolytics
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07K 5/1008: {the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala}
- C07K 5/101: {the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu}
- C07K 5/1019: {with the first amino acid being basic}
- C07K 5/1021: {with the first amino acid being acidic}
- C07K 5/1024: {with the first amino acid being heterocyclic}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A pharmaceutical composition comprising a synthetic neuromodulatory peptide is described. The invention discloses neuromodulatory peptides as defined in the claims and methods of using such molecules for therapeutic application. The neuromodulatory peptides included in the composition have been found to be effective in treatment of depression and other mood disorders, including anxiety.

## Claims

### Claim 1

A method for treating a mood disorder, comprising administering to a subject in need thereof a composition comprising a synthetic neuromodulatory peptide defined by the general formula I:
R1R2R3R4 (I)
wherein:
R1 is selected from the amino acids F, W, and D;
R2 is selected from the amino acids Q, D, and K;
R3 is selected from the amino acids S, Q, and T; and
R4 is selected from the amino acids E and V; and
the subject in need thereof is diagnosed with the mood disorder.

### Claim 2 (depends on 1)

The method of claim 1, wherein:
R1 is F;
R2 is Q;
R3 is S; and
R4 is E.

### Claim 3 (depends on 1)

The method of claim 1, wherein:
R1 is W;
R2 is D;
R3 is Q; and
R4 is V.

### Claim 4 (depends on 1)

The method of claim 1, wherein:
R1 is D;
R2 is K;
R3 is T; and
R4 is E.

### Claim 5 (depends on 1)

The method of claim 1, wherein the synthetic neuromodulatory peptide binds to a benzodiazepine binding site of a GABA-A receptor.

### Claim 6 (depends on 1)

The method of claim 1, wherein the synthetic neuromodulatory peptide binds to a neurosteroid binding site of a GABA-A receptor.

### Claim 7 (depends on 1)

The method of claim 1, wherein the synthetic neuromodulatory peptide binds to an α-β binding site of a GABA-A receptor.

### Claim 8 (depends on 1)

The method of claim 1, wherein the composition further comprises a pharmaceutically acceptable carrier or delivery vehicle.

### Claim 9 (depends on 8)

The method of claim 8, wherein the delivery vehicle is selected from a liposome, a nanoparticle, and a polysaccharide.

### Claim 10 (depends on 9)

The method of claim 9, wherein the polysaccharide is selected from cyclodextrin, chitosan, cellulose, and alginate.

### Claim 11 (depends on 1)

The method of claim 1, wherein the composition is administered orally, intranasally, intravenously or by inhalation.

### Claim 12 (depends on 1)

The method of claim 1, wherein the mood disorder is depression.

### Claim 13 (depends on 12)

The method of claim 12, wherein the depression is selected from major depressive disorder, dysthymia, breakthrough depression, treatment-refractory depression, depression associated with Parkinson's disease, depression associated with post-traumatic stress disorder, post-partum depression, bipolar depression, and suicidal ideation.

### Claim 14 (depends on 1)

The method of claim 1, wherein the mood disorder is an anxiety disorder.

### Claim 15 (depends on 14)

The method of claim 14, wherein the anxiety disorder is selected from separation anxiety disorder, selective mutism, specific phobia (SP), social anxiety disorder (SAD), panic disorder, agoraphobia, substance/medication-induced anxiety disorder, and anxiety disorder due to another medication condition, generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), postpartum depression (PPD), bipolar disorder or bipolar depression, obsessive-compulsive disorder (OCD), and attention deficit hyperactivity disorder (ADHD), social phobia, agitation in Alzheimer's disease, aggression in Alzheimer's disease, and obsessive-compulsive disorder.

### Claim 16 (depends on 1)

The method of claim 1, wherein the mood disorder is schizophrenia, a panic disorder, attention deficit hyperactivity disorder (ADHD), or a stress-related disorder.

### Claim 17 (depends on 1)

The method of claim 1, wherein the treatment further comprises administering an antidepressant, wherein the antidepressant is selected from the group consisting of serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, combined action SSRI/SNRI, serotonin-2 antagonist/reuptake inhibitors, an antidepressant with alpha-2 antagonism plus serotonin-2 and serotonin-3 antagonism, an antidepressant with serotonin/norepinephrine/dopamine reuptake inhibition, an antidepressant with norepinephrine and dopamine reuptake inhibition, 5-HT-1alpha antagonist, 5-HT-1beta antagonist, 5-HT1A receptor agonists, 5-HT1A receptor agonists and antagonists, 5-HT2 receptor antagonists, viloxazine hydrochloride, dehydroepiandosterone, NMDA receptor antagonists, AMPA receptor potentiators, substance P antagonists/neurokinin-1 receptor antagonists, nonpeptide Substance P antagonist, neurokinin 2 antagonists, neurokinin 3 antagonists, corticotropin-releasing factor receptor antagonists, antiglucocorticoid medications, glucocorticoid receptor antagonists, cortisol blocking agents, nitric oxide synthesize inhibitors, inhibitors of phosphodiesterase, enkephalinase inhibitors, GABA-A receptor agonists, free radical trapping agents, atypical MAOI's, selective MAOI inhibitors, hormones, folinic acid, leucovorin, tramadol, and tryptophan in combination with an antipsychotic drug, wherein said antipsychotic drug is selected from the group consisting of an atypical antipsychotic drug, and a dopamine system stabilizer.

### Claim 18 (depends on 1)

The method of claim 1, wherein the treatment further comprises administering an additional depression treatment, wherein the additional depression treatment is selected from one or more of amoxapine, bupropion, citalopram, clomipramine, desipramine, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, levomilnacipran, mesylate, methylphenidate, maprotiline, milnacipran, mirtazapine, nefazodone, nortriptyline, olanzapine, paroxetine, phenelzine, protriptyline, selegiline, sertraline, tranylcypromine, trimipramine, trazodone, venlafaxine, vilazodone, vortioxetine.

### Claim 19 (depends on 1)

The method of claim 1, wherein the treatment further comprises administering an additional anxiety treatment, wherein the additional anxiety treatment is selected from agent one or more of benzodiazepines selected from alprazolam, clonazepam, diazepam, lorazepam, oxazepam, and chlordiazepoxide; beta blockers selected from propranolol and atenolol; tricyclic antidepressants selected from imipramine, desipramine, nortriptyline, amitriptyline, doxepin, and clomipramine; monoamine oxidase inhibitors (MAOIs) selected from phenelzine, and tranylcypromine; selective serotonin reuptake inhibitors (SSRIs) selected from fluoxetine, fluvoxamine, sertraline, paroxetine, escitalopram oxalate, and citalopram; serotonin-norepinephrine reuptake inhibitors (SNRIs) selected from venlafaxine, venlafaxine extended release, and duloxetine; mild tranquilizers, the mild tranquilizer being buspirone; and anticonvulsants selected from valproate, pregabalin, and gabapentin.

### Claim 20 (depends on 1)

The method of claim 1, wherein the synthetic neuromodulatory peptide modulates voltage-gated calcium channels (VGCC) activity.