# US 2014/0154272 A1 · Compound and method for modulating opioid receptor activity > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2014/0154272 A1 - Document ID: US20140154272A1 - Status: Published application - Kind: A1 - Application number: 14/128,800 - Filed: 2012-06-22 - Published: 2014-06-05 - Earliest claimed: 2011-06-23 - Assignees: The Regents of the University of Michigan - Inventors: Henry I. Mosberg - Web page: https://patentgrep.com/patent/US20140154272A1 ## CPC - C07K 5/1016: {and aromatic or cycloaliphatic} - A61K 38/07: Tetrapeptides - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 23/00: Anaesthetics - A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] - C07K 7/06: having 5 to 11 amino acids - A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) - 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) - 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) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The invention provides a compound of formula (I), wherein R1 is H, C(NH)NH2, an amino acid, or a peptide; X is OH, NH2, NHR2, NR2R3, an amino acid, or a peptide; R2 and R3 are selected from alkyl, alkylenearyl, or alkyleneheteroaryl; each R4 and R5 is independently H or CH3; Z is 2-amino-2,3-dihydro-1H-indene-2-carboxylic acid; 2-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid; 6-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene 6-carboxylic acid; cyclohexylalanine; cyclohexylglycine; homophenylalanine; 1-naphthylalanine; 2-naphthylalanine; 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; or octahydro-1H-indole-2-carboxylic acid; n is 0, 1, 2, 3, or 4; with the proviso that X is not NH2 when R1 is H, R4 is H, R5 is CH3, Z is Aci, and n is 2; or a pharmaceutically acceptable salt, ester or solvate thereof. A method of treating pain and a method for treating a mu-opioid receptor mediated disorder and/or a delta-opioid receptor mediated disorder also are provided. ## Claims ### Claim 1 A compound having a structure of formula (I): wherein R1 is H, C(NH)NH2, an amino acid, or a peptide; X is OH, NH2, NHR2, NR2R3, an amino acid, or a peptide; R2 and R3 are the same or different and selected from alkyl, alkylenearyl, or alkyleneheteroaryl; each R4 and R5 is independently H or CH3; Z is an amino acid selected from the group consisting of 2-amino-2,3-dihydro-1H-indene-2-carboxylic acid (Aci); 2-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (Atc); 6-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene 6-carboxylic acid; cyclohexylalanine (Cha); cyclohexylglycine (Chg); homophenylalanine (Hfe); 1-naphthylalanine (1-Nal); 2-naphthylalanine (2-Nal); 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic); and octahydro-1H-indole-2-carboxylic acid (Oic); n is 0, 1, 2, 3, or 4; with the proviso that X is not NH2 when R1 is H, each R4 is H, each R5 is CH3, Z is Aci, and n is 2; or a pharmaceutically acceptable salt, ester or solvate thereof. ### Claim 2 (depends on 1) The compound of claim 1, wherein R1 is arginine. ### Claim 3 (depends on 1, 2) The compound of claim 1 or claim 2, wherein X is an amino acid selected from the group consisting of serine, threonine, arginine, homoarginine, and modified residues thereof. ### Claim 4 (depends on 1, 2, 3) The compound of any one of claims 1-3, wherein X is serine or threonine. ### Claim 5 (depends on 1, 2, 3) The compound of any one of claims 1-3, wherein X is a modified residue selected from the group consisting of serine, threonine, arginine, and homoarginine, and wherein the modified residue is substituted with one or more of NH2, OH, alkyl substituents, alkylenearyl substituents, alkyloxy substituents, and/or alkylenearyloxy substituents. ### Claim 6 (depends on 5) The compound of claim 5, wherein X is a modified arginine or homoarginine residue having the structure: wherein m is 1 or 2; R6 is selected from the group consisting of NH2, OH, and OR9; and R7, R8, and R9 are individually selected from the group consisting of alkyl substituents and alkylenearyl substituents. ### Claim 7 (depends on 1, 2, 3, 4, 5, 6) The compound of any one of claims 1-6, wherein R1 and/or X is a glycosylated amino acid or a glycosylated peptide. ### Claim 8 (depends on 1, 2, 3, 4, 5, 6, 7) The compound of any one of claims 1-7, wherein X is a glycosylated amino acid or glycosylated peptide comprising a glycosyl group selected from the group consisting of alpha and beta anomers of cellobiose, D-glucose, fucose, lactose, maltose, maltotriose, melibiose, and xylose. ### Claim 9 (depends on 1, 2, 3, 4, 5, 6, 7, 8) The compound of any one of claims 1-8, wherein R1 and/or X is a cell penetrating peptide. ### Claim 10 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9) The compound of any one of claims 1-9, wherein each R4 is H. ### Claim 11 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9) The compound of any one of claims 1-9, wherein one R4 is H and one R4 is CH3. ### Claim 12 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9) The compound of any one of claims 1-9, wherein each R4 is CH3. ### Claim 13 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) The compound of any one of claims 1-12, wherein each R5 is H. ### Claim 14 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) The compound of any one of claims 1-12, wherein one R5 is H and one R4 is CH3. ### Claim 15 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) The compound of any one of claims 1-12, wherein one R5 is H and one R5 is CH3. ### Claim 16 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) The compound of any one of claims 1-12, wherein each R5 is CH3. ### Claim 17 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) The compound of any one of claims 1-16, wherein n is 0. ### Claim 18 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) The compound of any one of claims 1-16, wherein n is 1. ### Claim 19 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) The compound of any one of claims 1-16, wherein n is 2. ### Claim 20 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) The compound of any one of claims 1-16, wherein n is 3. ### Claim 21 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) The compound of any one of claims 1-16, wherein n is 4. ### Claim 22 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) The compound of any one of claims 1-21, wherein Z is Aci. ### Claim 23 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) The compound of any one of claims 1-21, wherein Z is Atc. ### Claim 24 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) The compound of any one of claims 1-21, wherein Z is 6-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene 6-carboxylic acid. ### Claim 25 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) The compound of any one of claims 1-21, wherein Z is Cha. ### Claim 26 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) The compound of any one of claims 1-21, wherein Z is Chg. ### Claim 27 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) The compound of any one of claims 1-21, wherein Z is Hfe. ### Claim 28 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) The compound of any one of claims 1-21, wherein Z is 1-Nal. ### Claim 29 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) The compound of any one of claims 1-21, wherein Z is 2-Nal. ### Claim 30 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) The compound of any one of claims 1-21, wherein Z is Tic. ### Claim 31 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21) The compound of any one of claims 1-21, wherein Z is Oic. ### Claim 32 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) The compound of any one of claims 1-16 having a structure: ### Claim 33 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) The compound of any one of claims 1-16 having a structure: ### Claim 34 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) The compound of any one of claims 1-16 having a structure: ### Claim 35 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) The compound of any one of claims 1-16 having a structure: ### Claim 36 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) The compound of any one of claims 1-16 having a structure: ### Claim 37 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) The compound of any one of claims 1-16 having a structure: ### Claim 38 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) The compound of any one of claims 1-16 having a structure: ### Claim 39 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) The compound of any one of claims 1-16 having a structure: ### Claim 40 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) The compound of any one of claims 1-16 having a structure: ### Claim 41 (depends on 1) The compound of claim 1 having a structure: ### Claim 42 (depends on 1) The compound of claim 1 having a structure: ### Claim 43 (depends on 1) The compound of claim 1 having a structure: ### Claim 44 (depends on 1) The compound of claim 1 having a structure: ### Claim 45 (depends on 1) The compound of claim 1 having a structure: ### Claim 46 (depends on 1) The compound of claim 1 having a structure: ### Claim 47 (depends on 1) The compound of claim 1 having a structure: ### Claim 48 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47) The compound of any one of claims 1-47 conjugated to an entity that enhances the half life of the compound, enhances cellular uptake of the compound, and/or enhances transport across the blood-brain barrier. ### Claim 49 (depends on 48) The compound of claim 48, wherein the compound is conjugated to a water soluble polymer. ### Claim 50 (depends on 48) The compound of claim 48, wherein the compound is conjugated to albumin, an antibody or fragment thereof, or a proline-alanine-serine multimer (PASylation). ### Claim 51 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50) The compound of any one of claims 1-50, wherein the compound is a mu-opioid receptor (MOR) agonist and a delta-opioid receptor (DOR) antagonist. ### Claim 52 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51) The compound of any one of claims 1-51, wherein the compound displays substantially equivalent binding affinity for MOR and DOR. ### Claim 53 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52) The compound of any one of claims 1-52, wherein the compound binds MOR and DOR with an affinity at least 100 times greater than the compound binds kappa-opioid receptor (KOR). ### Claim 54 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53) A method of modulating the activity of MOR and/or DOR, the method comprising exposing a MOR and/or a DOR to the compound of any one of claims 1-53. ### Claim 55 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53) A composition comprising the compound of any one of claims 1-53 and a pharmaceutically acceptable carrier. ### Claim 56 (depends on 55) The composition of claim 55 further comprising one or more therapeutic agents. ### Claim 57 (depends on 55, 56) A method of treating pain in a subject, the method comprising administering to the subject the composition of claim 55 or claim 56 in an amount sufficient to induce analgesia. ### Claim 58 (depends on 55, 56, 57) The method of claim 57, wherein administration of the composition of claim 55 or claim 56 attenuates physical dependence or tolerance associated with opioid use. ### Claim 59 (depends on 55, 56) A method for treating a mu-opioid receptor (MOR) mediated disorder in a subject, the method comprising administering to the subject the composition of claim 55 or claim 56 in an amount sufficient to ameliorate the disorder. ### Claim 60 (depends on 55, 56) A method for treating a delta-opioid receptor (DOR) mediated disorder in a subject, the method comprising administering to the subject the composition of claim 55 or claim 56 in an amount sufficient to ameliorate the disorder. ### Claim 61 (depends on 55, 56) A method for treating a mu-opioid receptor (MOR) mediated disorder and a delta-opioid receptor (DOR) mediated disorder in a subject, the method comprising administering to the subject the composition of claim 55 or claim 56 in an amount sufficient to ameliorate the disorder. ### Claim 62 (depends on 57, 58, 59, 60, 61) The method of any one of claims 57-61, wherein the composition is administered intrathecally, intravenously, subcutaneously, intramuscularly, or orally. ### Claim 63 (depends on 57, 58, 59, 60, 61, 62) The method of any one of claims 57-62, further comprising administering to the subject an additional therapeutic agent and/or an agent that facilitates transport across the blood-brain barrier.