Receptor expression and signaling properties in the brain, and structural ligand motifs that contribute to delta opioid receptor agonist-induced seizures

Blaine, Arryn T.; Rijn, Richard M. van

doi:10.1016/j.neuropharm.2023.109526

Cited by 6 publications

(2 citation statements)

References 126 publications

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“…Nonetheless, δOR agonists free of proconvulsive behavior have been reported in the literature, albeit the precise mechanism of δOR agonist-induced seizures remains elusive. 21,22 Despite the long-held view that, with the exception of family C receptors, most GPCRs are functional as single monomeric units, a number of GPCRs in other families have been proposed to form dimers or even higher-order oligomers. 23 These include previous studies documenting the formation of μOR (or MOR) and δOR homodimers as well as higher-order homo-oligomers using biochemical methods on membrane preparations.…”

Section: ■ Introductionmentioning

confidence: 99%

“…In contrast, it is less effective than μOR-mediated agonism for acute conditions. , Furthermore, δOR agonism has been associated with inducing seizures, thus reducing the targets’ attractiveness for pain management. Nonetheless, δOR agonists free of proconvulsive behavior have been reported in the literature, albeit the precise mechanism of δOR agonist-induced seizures remains elusive. , …”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, and Characterization of New δ Opioid Receptor-Selective Fluorescent Probes and Applications in Single-Molecule Microscopy of Wild-Type Receptors

Drakopoulos,

Koszegi,

Seier

et al. 2024

J. Med. Chem.

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The delta opioid receptor (δOR or DOR) is a G protein-coupled receptor (GPCR) showing a promising profile as a drug target for nociception and analgesia. Herein, we design and synthesize new fluorescent antagonist probes with high δOR selectivity that are ideally suited for single-molecule microscopy (SMM) applications in unmodified, untagged receptors. Using our new probes, we investigated wild-type δOR localization and mobility at low physiological receptor densities for the first time. Furthermore, we investigate the potential formation of δOR homodimers, as such a receptor organization might exhibit distinct pharmacological activity, potentially paving the way for innovative pharmacological therapies. Our findings indicate that the majority of δORs labeled with these probes exist as freely diffusing monomers on the cell surface in a simple cell model. This discovery advances our understanding of OR behavior and offers potential implications for future therapeutic research.

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Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Characterization of New δ Opioid Receptor-Selective Fluorescent Probes and Applications in Single-Molecule Microscopy of Wild-Type Receptors

Drakopoulos,

Koszegi,

Seier

et al. 2024

J. Med. Chem.

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A novel cinnamic and caffeic acid‐conjugated peptide analogs with anticonvulsant and analgesic potency: Comparative analyses of trans/cis isomers

Tchekalarova,

Pechlivanova,

Rangelov

et al. 2024

Drug Development Research

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The novel cinnamic acid (CA) (H4‐CA, H5‐CA, and H7‐CA) and caffeic acid (KA) (H4‐KA, H5‐KA, and H7‐KA) hemorphin analogs have recently been synthesized and their trans isomers have been tested for antiseizure and antinociceptive activity. In the present study, the cis forms of these compounds were tested and compared with their trans isomers in seizure and nociception tests in mice. The cis‐H5‐CA and H7‐CA compounds showed efficacy against psychomotor seizures, whereas the trans isomers were ineffective. Both the cis and trans KA isomers were ineffective in the 6‐Hz test. In the maximal electroshock (MES) test, the cis isomers showed superior antiseizure activity to the trans forms of CA and KA conjugates, respectively. The suppression of seizure propagation by cis‐H5‐CA and the cis‐H5‐KA was reversed by a kappa opioid receptor (KOR) antagonist. Naloxone and naltrindole were not effective. The cis‐isomers of CA conjugates and cis‐H7‐KA produced significantly stronger antinociceptive effects than their trans‐isomers. The cis‐H5‐CA antinociception was blocked by naloxone in the acute phase and by naloxone and KOR antagonists in the inflammatory phase of the formalin test. The antinociception of the KA conjugates was not abolished by opioid receptor blockade. None of the tested conjugates affected the thermal nociceptive threshold. The results of the docking analysis also suggest a model‐specific mechanism related to the activity of the cis‐isomers of CA and KA conjugates in relation to opioid receptors. Our findings pave the way for the further development of novel opioid‐related antiseizure and antinociceptive therapeutics.

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Delta opioid receptor system

El Daibani,

Pradhan

2025

Migraine Pain Management

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Receptor expression and signaling properties in the brain, and structural ligand motifs that contribute to delta opioid receptor agonist-induced seizures

Cited by 6 publications

References 126 publications

Design, Synthesis, and Characterization of New δ Opioid Receptor-Selective Fluorescent Probes and Applications in Single-Molecule Microscopy of Wild-Type Receptors

Design, Synthesis, and Characterization of New δ Opioid Receptor-Selective Fluorescent Probes and Applications in Single-Molecule Microscopy of Wild-Type Receptors

A novel cinnamic and caffeic acid‐conjugated peptide analogs with anticonvulsant and analgesic potency: Comparative analyses of trans/cis isomers

Delta opioid receptor system

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