Design of enkephalin modifications protected from brain extracellular peptidases providing long-term analgesia

Kropotova, Ekaterina S.; Ivleva, Irina; Karpenko, Marina N.; Mosevitsky, Mark I.

doi:10.1016/j.bmc.2019.115184

Cited by 4 publications

(4 citation statements)

References 37 publications

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“…Another group [ 75 ] has shown that intranasal administration of enkephalins yields an analgesic effect in rodent pain models and that the analgesic effects could be enhanced by co-administration of enzyme inhibitors and/or absorption enhancers to reduce rapid destruction by extracellular peptidases. Another interesting approach is to design enkephalin derivatives that are more resistant against these peptidases and extend their half-lives [ 76 ].…”

Section: Other Polypeptides That Work As Analgesicsmentioning

confidence: 99%

Intranasal Administration for Pain: Oxytocin and Other Polypeptides

et al. 2021

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Pain, particularly chronic pain, remains one of the most debilitating and difficult-to-treat conditions in medicine. Chronic pain is difficult to treat, in part because it is associated with plastic changes in the peripheral and central nervous systems. Polypeptides are linear organic polymers that are highly selective molecules for neurotransmitter and other nervous system receptors sites, including those associated with pain and analgesia, and so have tremendous potential in pain therapeutics. However, delivery of polypeptides to the nervous system is largely limited due to rapid degradation within the peripheral circulation as well as the blood–brain barrier. One strategy that has been shown to be successful in nervous system deposition of polypeptides is intranasal (IN) delivery. In this narrative review, we discuss the delivery of polypeptides to the peripheral and central nervous systems following IN administration. We briefly discuss the mechanism of delivery via the nasal–cerebral pathway. We review recent studies that demonstrate that polypeptides such as oxytocin, delivered IN, not only reach key pain-modulating regions in the nervous system but, in doing so, evoke significant analgesic effects. IN administration of polypeptides has tremendous potential to provide a non-invasive, rapid and effective method of delivery to the nervous system for chronic pain treatment and management.

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Section: Other Polypeptides That Work As Analgesicsmentioning

confidence: 99%

Intranasal Administration for Pain: Oxytocin and Other Polypeptides

et al. 2021

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“…For a more detailed look at opioid receptor specific therapeutics please consult the following articles ( Broom et al, 2002 ; Spetea et al, 2013 ; Browne et al, 2020 ; Grim et al, 2020 ; Senese et al, 2020 ). To capitalize on the analgesic effects of endogenous Enks, research has been done to chemically modify Enks so they are more difficult to degrade and analgesic properties of endogenous Enks can be amplified while retaining their ligand specificity for MOR and DOR ( Pert et al, 1976 ; Kropotova et al, 2020 ). A result of these studies is the development of dual enkephalinase inhibitors (DENKIs) that enhance the analgesic effects of endogenous Enks only at sites of release, avoiding negative side effects including tolerance, respiratory depression, and constipation that derive from widespread MOR and DOR activation ( Poras et al, 2014 ).…”

Section: Neuropeptide Familiesmentioning

confidence: 99%

Neuropeptide System Regulation of Prefrontal Cortex Circuitry: Implications for Neuropsychiatric Disorders

Casello

Flores

Yarur

et al. 2022

Front. Neural Circuits

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Neuropeptides, a diverse class of signaling molecules in the nervous system, modulate various biological effects including membrane excitability, synaptic transmission and synaptogenesis, gene expression, and glial cell architecture and function. To date, most of what is known about neuropeptide action is limited to subcortical brain structures and tissue outside of the central nervous system. Thus, there is a knowledge gap in our understanding of neuropeptide function within cortical circuits. In this review, we provide a comprehensive overview of various families of neuropeptides and their cognate receptors that are expressed in the prefrontal cortex (PFC). Specifically, we highlight dynorphin, enkephalin, corticotropin-releasing factor, cholecystokinin, somatostatin, neuropeptide Y, and vasoactive intestinal peptide. Further, we review the implication of neuropeptide signaling in prefrontal cortical circuit function and use as potential therapeutic targets. Together, this review summarizes established knowledge and highlights unknowns of neuropeptide modulation of neural function underlying various biological effects while offering insights for future research. An increased emphasis in this area of study is necessary to elucidate basic principles of the diverse signaling molecules used in cortical circuits beyond fast excitatory and inhibitory transmitters as well as consider components of neuropeptide action in the PFC as a potential therapeutic target for neurological disorders. Therefore, this review not only sheds light on the importance of cortical neuropeptide studies, but also provides a comprehensive overview of neuropeptide action in the PFC to serve as a roadmap for future studies in this field.

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“…Replacing a peptide bond susceptible to peptidases with a dipeptide isostere such as olefin, ester, and triazole has also been a useful tool to increase peptide stability as well as conjugating with antibodies [ 47 , 49 , 50 ]. A recent study showed that β-Ala at the N -terminus of an ENK-like tetrapeptide amide resulted in longer analgesic effects owing to less accessibility of endopeptidases [ 51 ]. Another recent study showed that N α -guanidinyl group at the N -terminus, which mimics the ionic state of the parent peptide, significantly improved the stability and lipophilicity as well as affinity and potency, when combined with C -terminal tetrazolate and D Ala in guanidyl-Tyr- D Ala-Gly-Phe-Leu-tetrazole ( Figure 2 ) [ 52 ].…”

Section: Peptidomimetics For Opioid Receptorsmentioning

confidence: 99%

“…As a local variation of parent amide backbone, β-amino acids, γ-amino acids, β-dipeptidomimetics, and the other conformationally constrained non-natural amino acids ( Figure 7 ) have been simply applied to opioid peptides [ 51 , 258 ]. Insertion of one (β-amino acids) or two additional carbon atoms (γ-amino acids) into a peptide backbone changed the conformational structure, afforded the structural diversity by increasing diastereomers, and enhanced metabolic stability for prolonged in vivo effect [ 258 ].…”

Section: Peptidomimetics For Opioid Receptorsmentioning

confidence: 99%

Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery

Lee

2022

Biomolecules

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Despite various advantages, opioid peptides have been limited in their therapeutic uses due to the main drawbacks in metabolic stability, blood-brain barrier permeability, and bioavailability. Therefore, extensive studies have focused on overcoming the problems and optimizing the therapeutic potential. Currently, numerous peptide-based drugs are being marketed thanks to new synthetic strategies for optimizing metabolism and alternative routes of administration. This tutorial review briefly introduces the history and role of natural opioid peptides and highlights the key findings on their structure-activity relationships for the opioid receptors. It discusses details on opioid peptidomimetics applied to develop therapeutic candidates for the treatment of pain from the pharmacological and structural points of view. The main focus is the current status of various mimetic tools and the successful applications summarized in tables and figures.

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Design of enkephalin modifications protected from brain extracellular peptidases providing long-term analgesia

Cited by 4 publications

References 37 publications

Intranasal Administration for Pain: Oxytocin and Other Polypeptides

Intranasal Administration for Pain: Oxytocin and Other Polypeptides

Neuropeptide System Regulation of Prefrontal Cortex Circuitry: Implications for Neuropsychiatric Disorders

Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery

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