Engineering endomorphin drugs: state of the art

@article{Lazarus2012EngineeringED,
  title={Engineering endomorphin drugs: state of the art},
  author={L. Lazarus and Y. Okada},
  journal={Expert Opinion on Therapeutic Patents},
  year={2012},
  volume={22},
  pages={1 - 14}
}
  • L. Lazarus, Y. Okada
  • Published 2012
  • Chemistry, Medicine
  • Expert Opinion on Therapeutic Patents
Introduction: Although endomorphins-1 (EM-1; H-Tyr-Pro-Phe-Trp-NH2) and -2 (EM-2; H-Tyr-Pro-Phe-Phe-NH2) are primarily considered agonists for the μ-opioid receptor (MOR), systematic alterations to specific residues provided antagonists and ligands with mixed μ/δ-opioid properties, suitable for application to health-related topics. While the application of endomorphins as antinociceptive agents and numerous biological endpoints were experimentally delineated in laboratory animals and in vitro… Expand
Original endomorphin-1 analogues exhibit good analgesic effects with minimal implications for human sperm motility.
TLDR
It is found that analogues GAGP, activating μ-opioid receptor and partial δ-opIOid receptor, exhibit good analgesic effects with minimal implications for human sperm motility. Expand
Endomorphin analogues with mixed μ-opioid (MOP) receptor agonism/δ-opioid (DOP) receptor antagonism and lacking β-arrestin2 recruitment activity.
TLDR
Compounds 7 and 9 were opioids with potent mixed MOP receptor agonism/DOP receptor antagonism and devoid of β-arrestin2 recruitment activity and may offer a unique template for the discovery of potent analgesics that produce less respiratory depression, less gastrointestinal dysfunction and that have a lower propensity to induce tolerance and dependence compared with morphine. Expand
The development of CNS-active LRRK2 inhibitors using property-directed optimisation.
TLDR
The use of in silico modelling, extensive in vitro assays and resource-efficient in vivo techniques to produce GNE-7915 reflects a trend towards the concerted optimisation of potency, selectivity and pharmacokinetic properties in early-stage drug development. Expand
Dilemma of Addiction and Respiratory Depression in the Treatment of Pain: A Prototypical Endomorphin as a New Approach.
TLDR
CYT-1010 and other novel mu-opioid receptor agonists in clinical development are promising alternatives to conventional opioids that may offer the possibility of safer treatment of moderate to severe pain. Expand
Endomorphin analog analgesics with reduced abuse liability, respiratory depression, motor impairment, tolerance, and glial activation relative to morphine
TLDR
The results suggest that endomorphin analogs described here could provide gold standard pain relief mediated by selective MOR activation, but with remarkably safer side effect profiles compared to opioids like morphine. Expand
Synthesis and biological activity of lipophilic analogs of the cationic antimicrobial active peptide anoplin
TLDR
Structural activity studies revealed that the substitution of specific amino acids and the incorporation of lipophilic groups enhanced the amphipathic α‐helical conformation inducing better antimicrobial effects. Expand
Endomorphin-2 Inhibits the Activity of the Spinoparabrachial Projection Neuron through Presynaptic Mechanisms in the Spinal Dorsal Horn in Rats
TLDR
Applying EM2 to the SDH could produce analgesia through inhibiting the activities of the spinoparabrachial PNs in lamina I by reducing presynaptic neurotransmitters release from the primary afferent terminals. Expand
Mechanism Underlying the Analgesic Effect Exerted by Endomorphin-1 in the rat Ventrolateral Periaqueductal Gray
TLDR
The analgesic effect of EM1 is largely dependent on its potent inhibition on the inhibitory inputs to 5-HTergic neurons, which overwhelms EM1’s direct inhibitory effect on 5- HTergic neurons. Expand
Glial dysfunction and persistent neuropathic postsurgical pain
  • L. Block
  • Medicine
  • Scandinavian journal of pain
  • 2016
TLDR
A possible contributing mechanism for the transition from acute physiological pain to persistent pain involves low-grade inflammation in the central nervous system, glial dysfunction and subsequently an imbalance in the neuron–glial interaction that causes enhanced and prolonged pain transmission. Expand
...
1
2
...

References

SHOWING 1-10 OF 176 REFERENCES
Synthesis and in vitro evaluation of a library of modified endomorphin 1 peptides.
TLDR
Dmt provided a promising lead compound: [C8Laa-Dmt[1]]-Endo-1 is nine times more stable, >8-fold more permeable in Caco-2 cell monolayers, and exhibits 140-fold greater mu-opioid receptor affinity than K(imu)=0.08nM. Expand
Endomorphin-1 Analogues Containing β-Proline Are μ-Opioid Receptor Agonists and Display Enhanced Enzymatic Hydrolysis Resistance
In this paper we describe the synthesis and affinity toward the μ-opioid receptor of some tetrapeptides obtained from endomorphin-1, H-Tyr-Pro-Trp-Phe-NH2 (1), by substituting each amino acid in turnExpand
Design of δ-opioid peptide antagonists for emerging drug applications
Abstract The need for δ-receptor-selective opioid antagonists has led to their development based on structure–activity relationships of δ- and μ-opioid agonists. The unusual amino acidExpand
δ Opioidmimetic Antagonists: Prototypes for Designing a New Generation of Ultraselective Opioid Peptides
TLDR
Dmt-Tic opioidmimetic peptides represent a highly potent class of opioid peptide antagonists with greater potency than the nonopioid δ antagonist naltrindole and have potential application as clinical and therapeutic compounds. Expand
Opioid Peptides: Synthesis and Biological Activity of New Endomorphin Analogues
SummarySyntheses are described of new endomorphin 1 and 2 peptoid–peptide hybrids in which Tyr1 and either one or both Phe3 and Phe4 have been replaced by N-substituted-glycine. The preparation isExpand
Synthesis and binding activity of endomorphin-1 analogues containing β-amino acids
Abstract Endomorphin-1 (Tyr-Pro-Trp-PheNH2) has been proposed as the most potent endogenous ligand of the μ-opioid receptors. In this paper, we describe the synthesis of some endomorphin-1 basedExpand
[N-Allyl-Dmt1]-Endomorphins Are μ-Opioid Receptor Antagonists Lacking Inverse Agonist Properties
[N-Allyl-Dmt1]-endomorphin-1 and -2 ([N-allyl-Dmt1]-EM-1 and -2) are new selective μ-opioid receptor antagonists obtained by N-alkylation with an allyl group on the amino terminus ofExpand
Synthesis and biological evaluation of cyclic endomorphin-2 analogs
TLDR
The results demonstrate that cyclization might be a promising strategy to enhance bioavailability of peptides and may serve a role in the development of novel endomorphin analogs with increased therapeutic potential. Expand
Endomorphin-1 analogues containing beta-proline are mu-opioid receptor agonists and display enhanced enzymatic hydrolysis resistance.
TLDR
The synthesis and affinity toward the mu-opioid receptor of some tetrapeptides obtained from endomorphin-1, H-Tyr-Pro-Trp-Phe-NH(2) (1), by substituting each amino acid in turn with its homologue suggest that this novel class of endomorphIn-1 analogues may represent suitable candidates for the in vivo investigation as potential mu-operative receptor agonists. Expand
Synthesis and binding activity of endomorphin-1 analogues containing beta-amino acids.
TLDR
The synthesis of some endomorphin-1 based tetrapeptides in which a residue of the sequence Tyr-Pro-Trp-PheNH2 is replaced by the corresponding beta-isomer, which showed different affinities for the opioid receptors labeled with [3H]-DAMGO in rat brain membranes, depending on the beta-amino acid. Expand
...
1
2
3
4
5
...