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-10919939-B2
Publication Date
2021-02-16
Expiration Date
2031-07-08
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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 analogs of endomorphin. 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 analogs of endomorphin are metabolically stable peptides that provide improved analgesia-to-side-effect ratios relative to morphine, including reduced tolerance, respiratory depression, motor impairment, and abuse potential.
The problem being solved is the limitation of currently used opioids that activate the mu opioid receptor, which although effective in pain relief, cause significant negative side effects including abuse liability, respiratory depression, cognitive and motor impairment, and development of tolerance and hyperalgesia. Prior efforts to develop compounds with analgesic properties but reduced side effects have met limited success and many patients do not achieve adequate relief due to these issues. Additionally, natural endomorphin peptides showed promise but suffer from poor metabolic stability and poor solubility, thus the invention addresses the need for analogs with enhanced solubility and reduced side effect profiles.
The invention provides cyclic pentapeptide and hexapeptide analogs of endomorphins with a carboxy-terminal extension and side-chain to side-chain cyclization. These peptides exhibit increased solubility compared to similar tetrapeptide analogs while maintaining or improving mu opioid receptor affinity and selectivity, and favorable therapeutic ratios of analgesia to side effects. The analogs do not induce the proinflammatory glial activation, or receptor signaling pathways that are implicated in morphine-associated side effects such as tolerance and respiratory depression, thereby providing effective pain relief with reduced adverse effects.
Claims Coverage
The patent presents one main independent claim directed to cyclic peptides of Formula I, along with their salts, pharmaceutical compositions thereof, and methods of treatment. The inventive features include the peptide's structure, specific amino acid substitutions, and their pharmaceutical use.
Cyclic peptide structure of Formula I
A cyclic peptide comprising the sequence H-Tyr-cyclo[X1-X2-X3-X4]-X5, where cyclization occurs via an amide linkage between side chains of amino acids at positions X1 and X4, providing metabolic stability and receptor specificity.
Specific amino acid residues and substitutions
X1 is selected from acidic or basic D-amino acids such as D-Lys and D-Orn; X4 is selected from acidic amino acids including D-Asp, D-Glu, Asp, and Glu; X3 is selected from aromatic amino acids including Phe, D-Phe, and p-substituted Phe (with NO2, F, Cl, or Br). X5 can be an amidated amino acid, including Gly-NH2 or Arg-NH2, with R groups being hydrogen or alkyls such as methyl to isoheptyl.
Pharmaceutical composition comprising the cyclic peptide
Pharmaceutical formulations containing the cyclic peptide of Formula I or its salts, including acetate salts, suitable for administration to a subject.
Use of cyclic peptide in treating pain
Methods for treating pain by administering an analgesically effective amount of the cyclic peptide or its pharmaceutical compositions, including intravenous administration.
The patent claims cover cyclic peptide agonists of the mu opioid receptor with defined amino acid compositions and cyclization, pharmaceutical formulations thereof, and therapeutic methods for pain management leveraging these novel peptides which possess improved efficacy and reduced side effects.
Stated Advantages
Reduced tolerance development compared to morphine leading to improved long-term analgesic effectiveness.
Decreased respiratory depression enhancing the safety profile of opioid treatment.
Lower impairment of motor coordination and cognitive function.
Reduced abuse liability as demonstrated by absence of conditioned place preference and self-administration in animal models.
Enhanced solubility compared to similar tetrapeptide analogs, facilitating pharmaceutical formulation and administration.
Resistance to proinflammatory glial activation, including reduced activation of glial p38, CGRP, and P2X7 receptor signaling pathways, which contributes to reduced side effects and inflammatory complications.
Documented Applications
Treatment of acute and chronic pain through selective mu opioid receptor activation.
Relief from gastrointestinal disorders such as diarrhea.
Therapy for opioid drug dependence including use in patients with history of opioid substance abuse.
Use as antimigraine agents, immunomodulatory agents, immunosuppressive agents, and antiarthritic agents.
Competitive and quantitative assays for measuring mu opioid receptor levels or screening for molecules that bind mu opioid receptors.
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