Cyclization in Opioid Peptides

Piekielna, Justyna; Perlikowska, Renata; Gach, Katarzyna; Janecka, Anna

doi:10.2174/1389450111314070008

Cited by 27 publications

(26 citation statements)

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“…Over the years a great number of cyclic analogs of DOR-selective enkephalins and deltorphins [44,[50][51][52][53] and KOR-selective dynorphins [54,55] have been synthesized through a variety of strategies, including several types of sulfur-containing bridges, carbonyl linkages, guanidine bridges [see 56 for review].…”

Section: Cyclization In Opioid Peptidesmentioning

confidence: 99%

Cyclic Endomorphin Analogs in Targeting Opioid Receptors to Achieve Pain Relief

Janecka

Gentilucci

2014

Future Med. Chem.

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Endomorphins, the endogenous ligands of the µ-opioid receptor, are attractive candidates for opioid-based pain-relieving agents. These tetrapeptides, with their remarkable affinity for the µ-opioid receptor, display favorable antinociceptive activity when injected directly into the brain of experimental animals. However, the application of endomorphins as clinical analgesics has been impeded by their instability in body fluids and inability to reach the brain after systemic administration. Among numerous modifications of the endomorphin structure aimed at improving their pharmacological properties, cyclization can be viewed as an interesting option. Here, we have summarized recent advances in obtaining endomorphin-based cyclic peptide analogs.

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Section: Cyclization In Opioid Peptidesmentioning

confidence: 99%

Cyclic Endomorphin Analogs in Targeting Opioid Receptors to Achieve Pain Relief

Janecka

Gentilucci

2014

Future Med. Chem.

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“…The cyclization of linear peptides enhances proteolytic stability and bioavailability by limiting the peptide’s dynamic nature, reducing its hydrogen bonding capability, increasing lipophilicity, and lowering its hydrodynamic radius [44,45]. Therefore, the cyclic peptides become able to adopt better defined conformations compared to their linear variants which typically occur in a conformational equilibrium, and thus, pay lower entropy when binding to their respective receptors.…”

Section: Introductionmentioning

confidence: 99%

Cyclic Opioid Peptides

Remesic

Lee

Hruby³

2016

CMC

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For decades the opioid receptors have been an attractive therapeutic target for the treatment of pain. Since the first discovery of enkephalin, approximately a dozen endogenous opioid peptides have been known to produce opioid activity and analgesia, but their therapeutics have been limited mainly due to low blood brain barrier penetration and poor resistance to proteolytic degradation. One versatile approach to overcome these drawbacks is the cyclization of linear peptides to cyclic peptides with constrained topographical structure. Compared to their linear parents, cyclic analogues exhibit better metabolic stability, lower off-target toxicity, and improved bioavailability. Extensive structure-activity relationship studies have uncovered promising compounds for the treatment of pain as well as further elucidate structural elements required for selective opioid receptor activity. The benefits that come with employing cyclization can be further enhanced through the generation of polycyclic derivatives. Opioid ligands generally have a short peptide chain and thus the realm of polycyclic peptides has yet to be explored. In this review, a brief history of designing ligands for the opioid receptors, including classic linear and cyclic ligands, is discussed along with recent approaches and successes of cyclic peptide ligands for the receptors. Various scaffolds and approaches to improve bioavailability are elaborated on and concluded with a discourse towards polycyclic peptides.

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“…Thus, the discovery and/or development of potent analgesics that result in effective analgesia with fewer side-effects is greatly needed; and this has long been the holy grail of opioid research (Solé and Barany, 1992; Corbett et al, 2006). In recent years, different approaches have been explored to design and synthesize analogs of naturally occurring opioid peptides (i.e., dermorphin, endomorphins, and enkephalins) as potential substitutes of exogenous opioids for pain relief (Gentilucci, 2004; Janecka et al, 2010; Ribeiro et al, 2011c; Piekielna et al, 2013). Other alternative strategies targeting opioid-receptor have been addressed (Solé and Barany, 1992; Ribeiro et al, 2011c).…”

Section: Development Of New Ktp Derivativesmentioning

confidence: 99%

Pharmacological Potential of the Endogenous Dipeptide Kyotorphin and Selected Derivatives

2017

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The endogenous peptide kyotorphin (KTP) has been extensively studied since it was discovered in 1979. The dipeptide is distributed unevenly over the brain but the majority is concentrated in the cerebral cortex. The putative KTP receptor has not been identified yet. As many other neuropeptides, KTP clearance is mediated by extracellular peptidases and peptide transporters. From the wide spectrum of biological activity of KTP, analgesia was by far the most studied. The mechanism of action is still unclear, but researchers agree that KTP induces Met-enkephalins release. More recently, KTP was proposed as biomarker of Alzheimer disease. Despite all that, KTP limited pharmacological value prompted researchers to develop derivatives more lipophilic and therefore more prone to cross the blood–brain barrier (BBB), and also more resistant to enzymatic degradation. Conjugation of KTP with functional molecules, such as ibuprofen, generated a new class of compounds with additional biological properties. Moreover, the safety profile of these derivatives compared to opioids and their efficacy as neuroprotective agents greatly increases their pharmacological value.

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Cyclization in Opioid Peptides

Cited by 27 publications

References 0 publications

Cyclic Endomorphin Analogs in Targeting Opioid Receptors to Achieve Pain Relief

Cyclic Endomorphin Analogs in Targeting Opioid Receptors to Achieve Pain Relief

Cyclic Opioid Peptides

Pharmacological Potential of the Endogenous Dipeptide Kyotorphin and Selected Derivatives

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