scholarly journals Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics

2006 ◽  
Vol 8 (1) ◽  
pp. E118-E125 ◽  
Author(s):  
Subramaniam Ananthan
Keyword(s):  
Opioid Receptor ◽  
Opioid Ligands ◽  
Receptor Interactions ◽  
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 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.

ENKEPHALIN-INDUCED DESENSITIZATION OF ADENYLATE CYCLASE IN RECOMBINANT CV CELLS EXPRESSING A MOUSE δ-OPIOID RECEPTOR

Analgesia ◽  
1995 ◽  
Vol 1 (4) ◽  
pp. 603-606
Author(s):  
Vincent Nappey ◽  
Jean-luc Butour ◽  
Christiane Moisand ◽  
Claire Gaveriaux-Ruff ◽  
Brigitte Kieffer ◽  
...  
Keyword(s):  
Adenylate Cyclase ◽  
Opioid Receptor ◽  
Δ Opioid Receptor

Genetic Variation in δ-Opioid Receptor Associates with Increased β- and γ-Secretase Activity in the Late Stages of Alzheimer’s Disease

2015 ◽  
Vol 48 (2) ◽  
pp. 507-516 ◽  
Author(s):  
Timo Sarajärvi ◽  
Mikael Marttinen ◽  
Teemu Natunen ◽  
Tarja Kauppinen ◽  
Petra Mäkinen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variation ◽  
Opioid Receptor ◽  
Secretase Activity ◽  
Δ Opioid Receptor ◽  
Late Stages
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