scholarly journals Structural requirements for ligands of the δ-opioid receptor

2009 ◽  
Vol 74 (11) ◽  
pp. 1207-1217 ◽  
Author(s):  
Vuk Micovic ◽  
Milovan Ivanovic ◽  
Ljiljana Dosen-Micovic
Keyword(s):  
Opioid Receptor ◽  
Binding Pocket ◽  
Hydroxyl Group ◽  
Opioid Ligands ◽  
Chiral Compounds ◽  
Alkyl Groups ◽  
Selective Ligands ◽  
Ligand Interactions ◽  
Automated Docking ◽  
Δ Opioid Receptor

The ?-opioid receptor is sensitive to ligand geometry. In order to assist the synthesis of new ?-selective opioid ligands, the structure elements of ?-selective opioid ligands necessary for their effective binding were investigated. The automated docking procedure with a flexible ligand was used to simulate the binding of 17 ?-selective ligands to the ?-receptor. It was found that voluminous N-alkyl groups reduce the binding potency of naltrindole derivatives by preventing the ligands from adopting the preferred conformation in the receptor. This was confirmed by enantiospecific binding of chiral compounds where only one enantiomer adopts the naltrindole-like preferred conformation in the binding pocket. Voluminous groups replacing the hydroxyl group in the 3-hydroxybenzyl fragment of naltrindole analogs reduce the binding potency due to unfavorable steric interactions with the receptor. The two diastereoisomers of the potent ?-opioid ligand SNC80 confirmed the preferred binding conformation and the major receptor-ligand interactions.

scholarly journals Synthesis and Biological Activities of Cyclic Lanthionine Enkephalin Analogues:  δ-Opioid Receptor Selective Ligands.

2002 ◽  
Vol 45 (24) ◽  
pp. 5414-5414 ◽  
Author(s):  
Yosup Rew ◽  
Shelle Malkmus ◽  
Camilla Svensson ◽  
Tony L. Yaksh ◽  
Nga N. Chung ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Biological Activities ◽  
Enkephalin Analogues ◽  
Selective Ligands ◽  
Δ Opioid Receptor

scholarly journals Biased Opioid Ligands

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4257 ◽  
Author(s):  
Abdelfattah Faouzi ◽  
Balazs R. Varga ◽  
Susruta Majumdar
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Signal Transduction Pathway ◽  
Opioid Peptide ◽  
Nop Receptor ◽  
Biased Agonism ◽  
Opioid Ligands ◽  
Substance Abuse Disorders ◽  
Δ Opioid Receptor

Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Four types of opioid receptors have been described, including the μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor). Despite the proven success of opioids in treating pain, there are still some inherent limitations. All clinically approved MOR analgesics are associated with adverse effects, which include tolerance, dependence, addiction, constipation, and respiratory depression. On the other hand, KOR selective analgesics have found limited clinical utility because they cause sedation, anxiety, dysphoria, and hallucinations. DOR agonists have also been investigated but they have a tendency to cause convulsions. Ligands targeting NOP receptor have been reported in the preclinical literature to be useful as spinal analgesics and as entities against substance abuse disorders while mixed MOR/NOP receptor agonists are useful as analgesics. Ultimately, the goal of opioid-related drug development has always been to design and synthesize derivatives that are equally or more potent than morphine but most importantly are devoid of the dangerous residual side effects and abuse potential. One proposed strategy is to take advantage of biased agonism, in which distinct downstream pathways can be activated by different molecules working through the exact same receptor. It has been proposed that ligands not recruiting β-arrestin 2 or showing a preference for activating a specific G-protein mediated signal transduction pathway will function as safer analgesic across all opioid subtypes. This review will focus on the design and the pharmacological outcomes of biased ligands at the opioid receptors, aiming at achieving functional selectivity.

scholarly journals Location of the hydrophobic pocket in the binding site of fentanyl analogs in the µ-opioid receptor

2007 ◽  
Vol 72 (7) ◽  
pp. 643-654
Author(s):  
Ljiljana Dosen-Micovic ◽  
Milovan Ivanovic ◽  
Vuk Micovic
Keyword(s):  
Opioid Receptor ◽  
Binding Pocket ◽  
Receptor Model ◽  
Hydrophobic Pocket ◽  
Optimal Position ◽  
Alkyl Groups ◽  
Fentanyl Analogs ◽  
Position And Orientation ◽  
Cis And Trans ◽  
Opioid Receptor Agonists

Fentanyl is a highly potent and clinically widely used narcotic analgesic. The synthesis of its analogs remains a challenge in an attempt to develop highly selective ?-opioid receptor agonists with specific pharmacological properties. In this paper, the use of flexible molecular docking of several specific fentanyl analogs to the ?-opioid receptor model, in order to test the hypothesis that the hydrophobic pocket accommodates alkyl groups at position 3 of the fentanyl skeleton, is described. The stereoisomers of the following compounds were studied: cis- and trans-3-methylfentanyl, 3,3-dimethylfentanyl, cis- and trans-3-ethylfentanyl, cis- and trans-3-propylfentanyl, cis-3-isopropylfentanyl and cis-3-benzylfentanyl. The optimal position and orientation of these fentanyl analogs in the binding pocket of the ?-receptor, explaining their enantiospecific potency, were determined. It was found that the 3-alkyl group of cis-3R,4S and trans-3S,4S stereoisomers of all the active compounds occupies the hydrophobic pocket between TM5, TM6 and TM7, made up of the amino acids Trp318 (TM7), Ile322 (TM7), Ile301 (TM6) and Phe237 (TM5). However, the fact that this hydrophobic pocket can also accommodate the bulky 3-alkyl substituents of the two inactive compounds: cis-3-isopropylfentanyl, and cis-3-benzylfentanyl, indicates that this hydrophobic pocket in the employed receptor model is probably too large. .

Development of a lanthanide-based assay for detection of receptor–ligand interactions at the δ-opioid receptor

2005 ◽  
Vol 343 (2) ◽  
pp. 299-307 ◽  
Author(s):  
Heather L. Handl ◽  
Josef Vagner ◽  
Henry I. Yamamura ◽  
Victor J. Hruby ◽  
Robert J. Gillies
Keyword(s):  
Opioid Receptor ◽  
Receptor Ligand ◽  
Ligand Interactions ◽  
Δ Opioid Receptor

Synthesis and Biological Activities of Cyclic Lanthionine Enkephalin Analogues: δ-Opioid Receptor Selective Ligands

2002 ◽  
Vol 45 (17) ◽  
pp. 3746-3754 ◽  
Author(s):  
Yosup Rew ◽  
Shelle Malkmus ◽  
Camilla Svensson ◽  
Tony L. Yaksh ◽  
Nga N. Chung ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Biological Activities ◽  
Enkephalin Analogues ◽  
Selective Ligands ◽  
Δ Opioid Receptor

scholarly journals A Complete Assessment of Dopamine Receptor- Ligand Interactions through Computational Methods

Molecules ◽  
2019 ◽  
Vol 24 (7) ◽  
pp. 1196 ◽  
Author(s):  
Beatriz Bueschbell ◽  
Carlos Barreto ◽  
António Preto ◽  
Anke Schiedel ◽  
Irina Moreira
Keyword(s):  
Dopamine Receptor ◽  
Electrostatic Interactions ◽  
Specific Binding ◽  
Binding Pocket ◽  
Binding Mode ◽  
Receptor Subtypes ◽  
Receptor Ligand ◽  
Selective Ligands ◽  
Ligand Interactions ◽  
New Treatments

Background: Selectively targeting dopamine receptors (DRs) has been a persistent challenge in the last years for the development of new treatments to combat the large variety of diseases involving these receptors. Although, several drugs have been successfully brought to market, the subtype-specific binding mode on a molecular basis has not been fully elucidated. Methods: Homology modeling and molecular dynamics were applied to construct robust conformational models of all dopamine receptor subtypes (D1-like and D2-like). Fifteen structurally diverse ligands were docked. Contacts at the binding pocket were fully described in order to reveal new structural findings responsible for selective binding to DR subtypes. Results: Residues of the aromatic microdomain were shown to be responsible for the majority of ligand interactions established to all DRs. Hydrophobic contacts involved a huge network of conserved and non-conserved residues between three transmembrane domains (TMs), TM2-TM3-TM7. Hydrogen bonds were mostly mediated by the serine microdomain. TM1 and TM2 residues were main contributors for the coupling of large ligands. Some amino acid groups form electrostatic interactions of particular importance for D1R-like selective ligands binding. Conclusions: This in silico approach was successful in showing known receptor-ligand interactions as well as in determining unique combinations of interactions, which will support mutagenesis studies to improve the design of subtype-specific ligands.

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