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Special Issue "Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 31 May 2020.

Special Issue Editors

Prof. Dr. Mariana Spetea
E-Mail Website
Guest Editor
Institute of Pharmacy, Department of Pharmaceutical Chemistry, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria
Interests: opioid drug discovery; opioid receptors; opioid agonists; opioid antagonists; pain; analgesia
Special Issues and Collections in MDPI journals
Prof. Dr. Helmut Schmidhammer
E-Mail Website
Guest Editor
Institute of Pharmacy, Department of Pharmaceutical Chemistry, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria
Interests: medicinal chemistry; drug design; lead optimization; synthesis and analytics; synthetical methods; opioid drug discovery; structure–activity relationships; analgesics

Special Issue Information

Dear Colleagues,

The interest in opioid drugs such as morphine, the oldest analgesic drug known, has been maintained through the years. Identification of endogenous opioid peptides and their receptors (mu, delta, kappa, and nociceptin receptors), molecular cloning and elucidation of crystal structures of opioid receptors represent key milestones in opioid research. Activation of opioid receptors regulates several pharmacological responses with beneficial therapeutic as well as nonbeneficial effects. Medical use and misuse of opioids have strongly increased in the past decades, resulting in an opioid epidemic. Diverse chemical and pharmacological approaches have been used over the years to mitigate the deleterious effects of opioids.

This Special Issue aims to highlight present efforts in medicinal chemistry and pharmacology of innovative ligands targeting the opioid receptors as effective and safe therapeutics for human diseases where the opioid system plays a central role. Further, it wants to draw a special attention on advancing concepts in opioid drug discovery.

Central directions in opioid research include structure–activity/function relationships, biochemistry of the receptors, understanding of opioid receptor-mediated actions and the linkage between therapeutic effects, side effects and molecular mode of action, and new therapeutic opportunities and novel tools/technologies. The topics of this Special Issue cover drug design, molecular modeling and synthesis, structure–activity relationships on ligands with distinct properties (agonists, antagonists, partial agonists, biased agonists, allosteric modulators and ligands acting at multiple opioid receptors) or selective site of action (central, peripheral), drug screening, opioid pharmacology, pain research, animal models of diseases, and any other topics related to the field of opioid research.

This Special Issue welcomes original articles, short communications and review articles on recent advances and emerging concepts in opioid drug discovery and in general opioid research.

Prof. Dr. Mariana Spetea
Prof. Dr. Helmut Schmidhammer
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

•    Opioid drugs
•    Opioid receptors
•    Pain
•    CNS disorders
•    Natural and synthetic compounds
•    Small molecules and peptides
•    Agonists, antagonists, and partial agonists
•    Biased agonists and allosteric modulators
•    Bi- and multifunctional ligands
•    Drug design
•    Computer-aided drug design
•    Synthesis and analytics
•    Pharmacophore modeling and dynamics simulations
•    Structure–activity relationships
•    Pharmacodynamics and pharmacokinetics
•    Pharmacology
•    Signal transduction

Published Papers (2 papers)

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Research

Open AccessArticle
The Meta-Position of Phe4 in Leu-Enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors
Molecules 2019, 24(24), 4542; https://doi.org/10.3390/molecules24244542 - 12 Dec 2019
Abstract
As tool compounds to study cardiac ischemia, the endogenous δ-opioid receptors (δOR) agonist Leu5-enkephalin and the more metabolically stable synthetic peptide (d-Ala2, d-Leu5)-enkephalin are frequently employed. However, both peptides have similar pharmacological profiles that [...] Read more.
As tool compounds to study cardiac ischemia, the endogenous δ-opioid receptors (δOR) agonist Leu5-enkephalin and the more metabolically stable synthetic peptide (d-Ala2, d-Leu5)-enkephalin are frequently employed. However, both peptides have similar pharmacological profiles that restrict detailed investigation of the cellular mechanism of the δOR’s protective role during ischemic events. Thus, a need remains for δOR peptides with improved selectivity and unique signaling properties for investigating the specific roles for δOR signaling in cardiac ischemia. To this end, we explored substitution at the Phe4 position of Leu5-enkephalin for its ability to modulate receptor function and selectivity. Peptides were assessed for their affinity to bind to δORs and µ-opioid receptors (µORs) and potency to inhibit cAMP signaling and to recruit β-arrestin 2. Additionally, peptide stability was measured in rat plasma. Substitution of the meta-position of Phe4 of Leu5-enkephalin provided high-affinity ligands with varying levels of selectivity and bias at both the δOR and µOR and improved peptide stability, while substitution with picoline derivatives produced lower-affinity ligands with G protein biases at both receptors. Overall, these favorable substitutions at the meta-position of Phe4 may be combined with other modifications to Leu5-enkephalin to deliver improved agonists with finely tuned potency, selectivity, bias and drug-like properties. Full article
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Open AccessArticle
Synthesis and Pharmacological Evaluation of Hybrids Targeting Opioid and Neurokinin Receptors
Molecules 2019, 24(24), 4460; https://doi.org/10.3390/molecules24244460 - 05 Dec 2019
Abstract
Morphine, which acts through opioid receptors, is one of the most efficient analgesics for the alleviation of severe pain. However, its usefulness is limited by serious side effects, including analgesic tolerance, constipation, and dependence liability. The growing awareness that multifunctional ligands which simultaneously [...] Read more.
Morphine, which acts through opioid receptors, is one of the most efficient analgesics for the alleviation of severe pain. However, its usefulness is limited by serious side effects, including analgesic tolerance, constipation, and dependence liability. The growing awareness that multifunctional ligands which simultaneously activate two or more targets may produce a more desirable drug profile than selectively targeted compounds has created an opportunity for a new approach to developing more effective medications. Here, in order to better understand the role of the neurokinin system in opioid-induced antinociception, we report the synthesis, structure–activity relationship, and pharmacological characterization of a series of hybrids combining opioid pharmacophores with either substance P (SP) fragments or neurokinin receptor (NK1) antagonist fragments. On the bases of the in vitro biological activities of the hybrids, two analogs, opioid agonist/NK1 antagonist Tyr-[d-Lys-Phe-Phe-Asp]-Asn-d-Trp-Phe-d-Trp-Leu-Nle-NH2 (2) and opioid agonist/NK1 agonist Tyr-[d-Lys-Phe-Phe-Asp]-Gln-Phe-Phe-Gly-Leu-Met-NH2 (4), were selected for in vivo tests. In the writhing test, both hybrids showed significant an antinociceptive effect in mice, while neither of them triggered the development of tolerance, nor did they produce constipation. No statistically significant differences in in vivo activity profiles were observed between opioid/NK1 agonist and opioid/NK1 antagonist hybrids. Full article
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