ENKEPAHLIN ANALOGS WITH IMPROVED BIOAVAILABILITY

• US 20080019913A1
• Filed: 07/09/2007
• Published: 01/24/2008
• Est. Priority Date: 07/07/2006
• Status: Abandoned Application

• Current Assignee: University of Arizona Office of Technology Transfer (University of Arizona)
• Original Assignee: University of Arizona Office of Technology Transfer (University of Arizona)
• Inventors: Bilsky, Edward, Polt, Robin
• Application Number:
  US11/775,045
• Publication Number:
  US 20080019913A1
• Time in Patent Office: Days
• US Class Current: 424/9.2
• CPC Class Codes: 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
• CPC Class Codes: A61K 47/548 Phosphates or phosphonates, e.g. bone-seeking phospholipids A61K47/544
• CPC Class Codes: C07K 14/702 with at least 1 amino acid in D-form
• CPC Class Codes: G01N 2500/00 Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 33/9486 Analgesics, e.g. opiates, aspirine

Abstract

Peptides having improved bioavailability, especially analogs of enkephalins, with biousian properties which have two conformations or two conformation ensembles with different solubility properties.

Claims

1. A DAMGO ([D-Ala²,Me-Phe⁴Gly⁵(ol)]enkephalin) analog in which one or more positions in formula I is substituted with a hydrophilic group that increases the hydrophilicity of the DAMGO analog compared to DAMGO;

wherein DAMGO is represented by formula (I);

2. The DAMGO analog of claim 1, which comprises a hydrophilic moiety at its C-terminus other than unsubstituted glycinol.

3. The DAMGO analog of claim 1, wherein the hydroxy group on the glycinol moiety is substituted with a group more hydrophilic than hydroxy.

4. The DAMGO analog of claim 1, wherein glycinol is replaced with an amino acid residue or modified amino acid residue more hydrophilic than glycinol.

5. The DAMGO analog of claim 1, which comprises the following structure:

wherein R is hydrogen or a hydrophilic group.

6. The DAMGO analog of claim 4, wherein R is a sugar or carbohydrate group.

7. The DAMGO analog of claim 4, wherein R comprises a phosphate, pyrophosphate, phosphonate, sulfate, or sulfonate group, which groups may be further substituted with alkyl, cycloalkyl or aryl.

8. The DAMGO analog of claim 1, wherein the glycinol moiety is replaced by L-serine amide, L-serine amide β

-D-xyloside, L-serine amide β

-D-glucoside, or L-serine amide β

-lactoside.

9. The DAMGO analog of claim 1 having one of the following structures:

10. The DAMGO analog of claim 1 having one of the following structures:

11. The DAMGO analog of claim 1 which is a mu opioid agonist, inverse agonist, or antagonist.

12. The DAMGO analog of claim 1 in which the degree of glycosylation ranges from 1.25 to 1.75 in terms of hydrodynamic glucose units or ranges between 0.75 to 0.90 g. u. in terms of surface-derived amphipathicity values.

13. The DAMGO analog of claim 1 which has a molecular mass of about 1,000 Da or less or which may contain up to 9 amino acid residues.

14. The DAMGO analog of claim 1 which has a lower binding affinity for the post-synaptic membrane than DAMGO.

15. The DAMGO analog of claim 1 which has a lower binding affinity for opioid mu receptor than DAMGO.

16. The DAMGO analog of claim 1 which penetrates the blood brain barrier faster or to a greater extent than DAMGO.

17. The DAMGO analog of claim 1 further comprising a modification to increase its biological half-life, biological adsorption, or passage across the blood brain barrier.

18. A pharmaceutical composition comprising the DAMGO analog of claim 1 and at least one pharmaceutically acceptable carrier or excipient.

19. A pharmaceutical composition comprising a liposome or lipid bilayer in which the DAMGO analog of claim 1 is present, wherein said DAMGO analog has been modified to incorporate into said liposome or lipid bilayer.

20. A method for relieving or modulating pain or for inducing analgesia or sedation comprising administering an effective amount of the DAMGO analog of claim 1 to a subject in need thereof.

21. A method for reducing blood pressure, respiration, or decreasing bowel motility comprising administering an effective amount of the DAMGO analog of claim 1 to a subject in need thereof.

22. A method for modulating itching, nausea, euphoria, or miosis (constricted pupils) comprising administering to a subject in need thereof an effective amount of the DAMGO analog of claim 1.

23. A method for treating a disease or disorder mediated by a mu opioid receptor comprising administering to a subject in need thereof an effective amount of the DAMGO analog of claim 1.

24. A method for identifying a DAMGO analog that binds to the mu opioid receptor and which exhibits biousian properties compared to DAMGO, comprising:

determining the ability of said analog to hop from one membrane surface to another, its ability to assume either a hydrophilic and hydrophobic configuration and/or its ability to freely diffuse throughout the aqueous compartments of a biologic organism,

selecting a DAMGO analog having a greater ability to hop from one membrane surface to another, a greater ability to assume both a hydrophilic and hydrophobic configuration, or a greater ability to freely diffuse throughout the aqueous compartments of the biologic organism, compared to DAMGO, and

selecting a DAMGO analog that binds to the mu opioid receptor.

25. The method of claim 24, wherein said DAMGO analog comprises:

where R is H or a hydrophilic group.

26. The method of claim 24, wherein membrane hopping ability or its biousian property is determined by at least one method selected from the group consisting of reversed-phase HPLC retention times;

Langmuir isotherms to lipophilic surfaces;

data from surface plasmon resonance (SPR);

vesicle binding using microcalorimetry; and

binding to micelles and bicelles using nuclear magnetic resonance (NMR) or circular dichroism (CD).