https://hal.archives-ouvertes.fr/hal-02437989/document

Opioid receptors: distinct roles in mood disorders

Delta opioid receptors in brain function and diseases.

Opioids are among the most effective analgesics available and are the first choice in the treatment of acute severe pain. However, partial efficacy, a tendency to produce tolerance, and a host of ill-tolerated side effects make clinically available opioids less effective in the management of chronic pain syndromes. Given that most therapeutic opioids produce their actions via µ-opioid receptors (MOPrs), other targets are constantly being explored, among which δ-opioid receptors (DOPrs) are being increasingly considered as promising alternatives. This review addresses DOPrs from the perspective of cellular and molecular determinants of their pharmacological diversity. Thus, DOPr ligands are examined in terms of structural and functional variety, DOPrs' capacity to engage a multiplicity of canonical and noncanonical G protein-dependent responses is surveyed, and evidence supporting ligand-specific signaling and regulation is analyzed. Pharmacological DOPr subtypes are examined in light of the ability of DOPr to organize into multimeric arrays and to adopt multiple active conformations as well as differences in ligand kinetics. Current knowledge on DOPr targeting to the membrane is examined as a means of understanding how these receptors are especially active in chronic pain management. Insight into cellular and molecular mechanisms of pharmacological diversity should guide the rational design of more effective, longer-lasting, and better-tolerated opioid analgesics for chronic pain management.

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Molecular Pharmacology of δ-Opioid Receptors

Delta opioid receptors represent a promising target for the development of novel analgesics. A number of tools have been developed recently that have significantly improved our knowledge of δ receptor function in pain control. These include several novel δ agonists with potent analgesic properties, and genetic mouse models with targeted mutations in the δ opioid receptor gene. Also, recent findings have further documented the regulation of δ receptor function at cellular level, which impacts on the pain-reducing activity of the receptor. These regulatory mechanisms occur at transcriptional and post-translational levels, along agonist-induced receptor activation, signaling and trafficking, or in interaction with other receptors and neuromodulatory systems. All these tools for in-vivo research, and proposed mechanisms at molecular level, have tremendously increased our understanding of δ receptor physiology, and contribute to designing innovative strategies for the treatment of chronic pain and other diseases such as mood disorders.

Delta opioid receptor analgesia: recent contributions from pharmacology and molecular approaches.

Faster, better, stronger: towards new antidepressant therapeutic strategies.

The novel δ opioid receptor agonist KNT-127 produces antidepressant-like and antinociceptive effects in mice without producing convulsions.

Synthesis of new opioid derivatives with a propellane skeleton and their pharmacology: part 1.

Acetylcholinesterase inhibitor (−)-homogalanthamine 3 was synthesized from μ opioid antagonist naltrexone (2) in 16% total yield. The synthesis features Grob fragmentation as a key reaction, which was especially accelerated in the presence of 15-crown-5.

Synthesis of (−)-Homogalanthamine from Naltrexone

Opioid δ1 receptor antagonist 7-benzylidenenaltrexone as an effective resistance reverser for chloroquine-resistant Plasmodium chabaudi

Synthesis of novel triplet drugs with 1,3,5-trioxazatriquinane skeletons and their pharmacologies. Part 2: Synthesis of novel triplet drugs with the epoxymethano structure (capped homotriplet).

Hiroshi Nagase

Papers

The novel δ opioid receptor agonist KNT-127 produces antidepressant-like and antinociceptive effects in mice without producing convulsions.

Synthesis of new opioid derivatives with a propellane skeleton and their pharmacology: part 1.

Synthesis of (−)-Homogalanthamine from Naltrexone

Opioid δ1 receptor antagonist 7-benzylidenenaltrexone as an effective resistance reverser for chloroquine-resistant Plasmodium chabaudi

Synthesis of novel triplet drugs with 1,3,5-trioxazatriquinane skeletons and their pharmacologies. Part 2: Synthesis of novel triplet drugs with the epoxymethano structure (capped homotriplet).