Mu opioid receptor agonist analogs of the endomorphins
Inventors
Zadina, James E. • Hackler, Laszlo
Assignees
Tulane University • US Department of Veterans Affairs
Publication Number
US-8716436-B2
Publication Date
2014-05-06
Expiration Date
2031-07-08
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
The invention relates to cyclic peptide agonists that bind to the mu (morphine) opioid receptor and their use in the treatment of acute and/or chronic pain. Embodiments of the invention are directed to cyclic pentapeptide and hexapeptide analogs of endomorphin that have (i) a carboxy-terminal extension with an amidated hydrophilic amino acid and (ii) a substitution in amino acid position 2. These peptide analogs exhibit decreased tolerance relative to morphine, increased solubility compared to similar tetrapeptide analogs, while maintaining favorable or improved therapeutic ratios of analgesia to side effects.
Core Innovation
The invention relates to cyclic peptide agonists that bind to the mu opioid receptor and their use in the treatment of acute and chronic pain. These cyclic pentapeptide and hexapeptide analogs of endomorphin have a carboxy-terminal extension with an amidated hydrophilic amino acid and a substitution in amino acid position 2. They exhibit decreased tolerance relative to morphine, increased solubility compared to similar tetrapeptide analogs, while maintaining favorable or improved therapeutic ratios of analgesia to side effects.
The problem being solved is the limitations of current opioid use due to negative side effects such as abuse liability, respiratory depression, and cognitive and motor impairment. Existing opioids often result in tolerance, dependence, and significant side effects, and alternatives have been met with similar problems. There is a growing unmet need for opioids that reduce motor and cognitive impairment, especially in the elderly, and improve safety while maintaining analgesic efficacy. Prior tetrapeptide analogs of endomorphins showed promise but had issues with solubility and side-effect profiles. The instant invention addresses these shortcomings by providing peptide analogs with unexpectedly better solubility and improved side-effect profiles.
Claims Coverage
The patent includes three main inventive features derived from independent claims focused on specific cyclic peptides, pharmaceutical compositions, and methods of treatment with these peptides.
Specific cyclic peptide sequences
The invention provides cyclic peptides consisting of the amino acid sequences Tyr-c[D-Lys-Trp-Phe-Glu]-NH2 (SEQ ID NO:1) or Tyr-c[D-Lys-Trp-Phe-Asp]-NH2 (SEQ ID NO:5). These peptides are novel cyclic endomorphin analogs with enhanced therapeutic properties.
Pharmaceutical compositions comprising said peptides
Pharmaceutical compositions containing a pharmaceutically acceptable carrier combined with the specific cyclic peptides of the invention are claimed, enabling administration for therapeutic use.
Methods of treating pain using the peptides
Methods are claimed for treating pain by administering an analgesic amount of the specific peptides. Additional inventive features include concurrent or alternating administration of an opioid drug, parenteral administration, and dosing regimens involving increasing doses to achieve and maintain full antinociception.
The claims collectively cover the specific peptide compounds, their pharmaceutical formulations, and their use in pain treatment protocols, including flexible dosing and combination therapies with other opioids.
Stated Advantages
Reduced tolerance development compared to morphine, allowing for prolonged effective analgesia.
Increased solubility relative to prior tetrapeptide analogs, facilitating improved pharmaceutical delivery.
Maintains or enhances analgesic efficacy while producing reduced respiratory depression compared to morphine.
Reduced motor and cognitive impairments relative to morphine, important for populations such as the elderly and military personnel.
Lower abuse liability, as demonstrated by lack of conditioned place preference in animal models.
Significantly greater potency and longer duration of action in treating neuropathic and chronic pain conditions compared to morphine.
Reduced glial activation and associated inflammatory responses after chronic administration, linked to decreased opioid-induced hyperalgesia and tolerance.
Documented Applications
Treatment of acute and/or chronic pain including neuropathic, post-incisional (post-operative), and inflammatory pain.
Relief from gastrointestinal disorders such as diarrhea.
Therapy for opioid drug dependence.
Use as analgesic agents with improved safety profiles including reduced respiratory depression and cognitive impairment.
Potential use as antimigraine agents, immunomodulatory agents, immunosuppressive agents, and antiarthritic agents.
Interested in licensing this patent?