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Synthesis and Application of Opioids

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

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 23732

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Prof. Dr. Susanna Fürst

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Guest Editor

Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Interests: opioid drugs; stimulants

Prof. Dr. Al-Khrasani Mahmoud

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Guest Editor

Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary
Interests: In vitro and vivo opioid pharmacology, in vitro pharmacology and applied biochemistry (isolated organs, brain slices, calcium imaging)

Special Issue Information

Dear Colleagues,

Opioids are a class of drugs that include the illegal drug heroin; synthetic opioids such as fentanyl; and pain relievers available legally by prescription, such as oxycodone (OxyContin®), hydrocodone (Vicodin®), codeine, morphine, and many others. Medically, they are primarily used for pain relief, including anesthesia. Other medical uses include the suppression of diarrhea, replacement therapy for opioid use disorder, reversing opioid overdose, and suppressing cough. Opioids act by binding to opioid receptors, which are found principally in the central and peripheral nervous systems and the gastrointestinal tract. These receptors mediate both the psychoactive and the somatic effects of opioids.

The topics of this Special Issue cover drug design, molecular modeling and synthesis, structure–activity relationships on ligands with distinct properties or selective site of action (central, peripheral), drug screening, opioid pharmacology, pain research, animal models of disease, and any other topics related to the field of opioid research.

Prof. Dr. Susanna Fürst
Prof. Dr. Al-Khrasani Mahmoud
Guest Editors

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Keywords

opioids
opioid pharmacology
small molecules and peptides
neuropharmacology

Published Papers (12 papers)

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16 pages, 6122 KiB

Open AccessArticle

New Insights into the Opioid Analgesic Profile of cis-(−)-N-Normetazocine-derived Ligands

by Giuliana Costanzo, Rita Turnaturi, Carmela Parenti, Salvatore Spoto, Silvia Piana, Maria Dichiara, Chiara Zagni, Anna Rita Galambos, Nariman Essmat, Agostino Marrazzo, Emanuele Amata, Mahmoud Al-Khrasani and Lorella Pasquinucci

Molecules 2023, 28(12), 4827; https://doi.org/10.3390/molecules28124827 - 17 Jun 2023

Cited by 1 | Viewed by 949

Abstract

In this work, we report on the in vitro and in vivo pharmacological properties of LP1 analogs to complete the series of structural modifications aimed to generate compounds with improved analgesia. To do that, the phenyl ring in the N-substituent of our lead compound LP1 was replaced by an electron-rich or electron-deficient ring and linked through a propanamide or butyramide spacer at the basic nitrogen of the (−)-cis-N-normetazocine skeleton. In radioligand binding assays, compounds 3 and 7 were found to display nanomolar binding affinity for the μ opioid receptor (MOR) (K_i = 5.96 ± 0.08 nM and 1.49 ± 0.24 nM, respectively). In the mouse vas deferens (MVD) assay, compound 3 showed an antagonist effect against DAMGO ([D-Ala², N-MePhe⁴, Gly-ol]-enkephalin), a highly selective MOR prototype agonist, whereas compound 7 produced naloxone reversible effect at MOR. Moreover, compound 7, as potent as LP1 and DAMGO at MOR, was able to reduce thermal and inflammatory pain assessed by the mouse tail-flick test and rat paw pressure thresholds (PPTs) measured by a Randall–Selitto test. Full article

(This article belongs to the Special Issue Synthesis and Application of Opioids)

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18 pages, 2125 KiB

Open AccessArticle

Solid-Phase Synthesis of the Bicyclic Peptide OL-CTOP Containing Two Disulfide Bridges, and an Assessment of Its In Vivo μ-Opioid Receptor Antagonism after Nasal Administration

by Ramanjaneyulu Rayala, Annika Tiller, Shahayra A. Majumder, Heather M. Stacy, Shainnel O. Eans, Aleksandra Nedovic, Jay P. McLaughlin and Predrag Cudic

Molecules 2023, 28(4), 1822; https://doi.org/10.3390/molecules28041822 - 15 Feb 2023

Cited by 1 | Viewed by 2150

Abstract

New strategies facilitate the design of cyclic peptides which can penetrate the brain. We have designed a bicyclic peptide, OL-CTOP, composed of the sequences of a selective μ-opioid receptor antagonist, CTOP (f-cyclo(CYwOTX)T) (X = penicillamine, Pen; O = ornithine) and odorranalectin, OL (YASPK-cyclo(CFRYPNGVLAC)T), optimized its solid-phase synthesis and demonstrated its ability for nose-to-brain delivery and in vivo activity. The differences in reactivity of Cys and Pen thiol groups protected with trityl and/or acetamidomethyl protecting groups toward I₂ in different solvents were exploited for selective disulfide bond formation on the solid phase. Both the single step and the sequential strategy applied to macrocyclization reactions generated the desired OL-CTOP, with the sequential strategy yielding a large quantity and better purity of crude OL-CTOP. Importantly, intranasally (i.n.s.) administered OL-CTOP dose-dependently antagonized the analgesic effect of morphine administered to mice through the intracerebroventricular route and prevented morphine-induced respiratory depression. In summary, the results demonstrate the feasibility of our solid-phase synthetic strategy for the preparation of the OL-CTOP bicyclic peptide containing two disulfide bonds and reveal the potential of odorranalectin for further modifications and the targeted delivery to the brain. Full article

(This article belongs to the Special Issue Synthesis and Application of Opioids)

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24 pages, 2462 KiB

Open AccessArticle

Solving an Old Puzzle: Elucidation and Evaluation of the Binding Mode of Salvinorin A at the Kappa Opioid Receptor

by Kristina Puls and Gerhard Wolber

Molecules 2023, 28(2), 718; https://doi.org/10.3390/molecules28020718 - 11 Jan 2023

Cited by 4 | Viewed by 2357

Abstract

The natural product Salvinorin A (SalA) was the first nitrogen-lacking agonist discovered for the opioid receptors and exhibits high selectivity for the kappa opioid receptor (KOR) turning SalA into a promising analgesic to overcome the current opioid crisis. Since SalA’s suffers from poor pharmacokinetic properties, particularly the absence of gastrointestinal bioavailability, fast metabolic inactivation, and subsequent short duration of action, the rational design of new tailored analogs with improved clinical usability is highly desired. Despite being known for decades, the binding mode of SalA within the KOR remains elusive as several conflicting binding modes of SalA were proposed hindering the rational design of new analgesics. In this study, we rationally determined the binding mode of SalA to the active state KOR by in silico experiments (docking, molecular dynamics simulations, dynophores) in the context of all available mutagenesis studies and structure-activity relationship (SAR) data. To the best of our knowledge, this is the first comprehensive evaluation of SalA’s binding mode since the determination of the active state KOR crystal structure. SalA binds above the morphinan binding site with its furan pointing toward the intracellular core while the C2-acetoxy group is oriented toward the extracellular loop 2 (ECL2). SalA is solely stabilized within the binding pocket by hydrogen bonds (C210^ECL2, Y312^7.35, Y313^7.36) and hydrophobic contacts (V118^2.63, I139^3.33, I294^6.55, I316^7.39). With the disruption of this interaction pattern or the establishment of additional interactions within the binding site, we were able to rationalize the experimental data for selected analogs. We surmise the C2-substituent interactions as important for SalA and its analogs to be experimentally active, albeit with moderate frequency within MD simulations of SalA. We further identified the non-conserved residues 2.63, 7.35, and 7.36 responsible for the KOR subtype selectivity of SalA. We are confident that the elucidation of the SalA binding mode will promote the understanding of KOR activation and facilitate the development of novel analgesics that are urgently needed. Full article

(This article belongs to the Special Issue Synthesis and Application of Opioids)

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22 pages, 4250 KiB

Open AccessArticle

Synthesis and Pharmacological Evaluation of Enantiopure N-Substituted Ortho-c Oxide-Bridged 5-Phenylmorphans

by Fuying Li, Theresa A. Kopajtic, Jonathan L. Katz, Dan Luo, Thomas E. Prisinzano, Gregory H. Imler, Jeffrey R. Deschamps, Arthur E. Jacobson and Kenner C. Rice

Molecules 2022, 27(24), 8808; https://doi.org/10.3390/molecules27248808 - 12 Dec 2022

Cited by 1 | Viewed by 1322

Abstract

The design of enantiopure stereoisomers of N-2-phenylcyclopropylmethyl-substituted ortho-c oxide-bridged phenylmorphans, the E and Z isomers of an N-cinnamyl moiety, and N-propyl enantiomers were based on combining the most potent oxide-bridged phenylmorphan (the ortho-c isomer) with the most potent N-substituent that we previously found with a 5-(3-hydroxy)phenylmorphan (i.e., N-2-phenylcyclopropyl methyl moieties, N-cinnamyl, and N-propyl substituents). The synthesis of the eight enantiopure N-2-phenylcyclopropylmethyl ortho-c oxide-bridged phenylmorphans and six additional enantiomers of the N-substituted ortho-c oxide-bridged phenylmorphans (N-E and Z-cinnamyl compounds, and N-propyl compounds) was accomplished. The synthesis started from common intermediates (3R,6aS,11aS)-10-methoxy-1,3,4,5,6,11a-hexahydro-2H-3,6a-methano-benzofuro[2,3-c]azocine (+)-6 and its enantiomer, (3S, 6aR, 11aR)-(-)-6, respectively. The enantiomers of ±-6 were obtained through salt formation with (S)-(+)- and (R)-(-)-p-methylmandelic acid, and the absolute configuration of the (R)-(-)-p-methylmandelate salt of (3S, 6aR, 11aR)-(-)-6 was determined by single-crystal X-ray analysis. The enantiomeric secondary amines were reacted with N-(2-phenylcyclopropyl)methyl derivatives, 2-(E)-cinnamyl bromide, and (Z)-3-phenylacrylic acid. These products led to all of the desired N-derivatives of the ortho-c oxide-bridged phenylmorphans. Their opioid receptor binding affinity was measured. The compounds with MOR affinity < 50 nM were examined for their functional activity in the forskolin-induced cAMP accumulation assay. Only the enantiomer of the N-phenethyl ortho-c oxide-bridged phenylmorphan ((-)-1), and only the (3S,6aR,11aR)-2-(((1S,2S)-2-phenylcyclopropyl)methyl)-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol isomer ((+)-17), and the N-phenylpropyl derivative ((-)-25) had opioid binding affinity < 50 nM. Both (-)-1 and (-)-25 were partial agonists in the cAMP assay, with the former showing high potency and low efficacy, and the latter with lower potency and less efficacy. Most interesting was the N-2-phenylcyclopropylmethyl (3S,6aR,11aR)-2-(1S,2S)-enantiomer ((+)-17). That compound had good MOR binding affinity (Ki = 11.9 nM) and was found to have naltrexone-like potency as a MOR antagonist (IC₅₀ = 6.92 nM). Full article

(This article belongs to the Special Issue Synthesis and Application of Opioids)

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11 pages, 1151 KiB

Open AccessArticle

Bifunctional Peptidomimetic G Protein-Biased Mu-Opioid Receptor Agonist and Neuropeptide FF Receptor Antagonist KGFF09 Shows Efficacy in Visceral Pain without Rewarding Effects after Subcutaneous Administration in Mice

by Maria Dumitrascuta, Charlotte Martin, Steven Ballet and Mariana Spetea

Molecules 2022, 27(24), 8785; https://doi.org/10.3390/molecules27248785 - 11 Dec 2022

Cited by 3 | Viewed by 1426

Abstract

There is still an unmet clinical need to develop new pharmaceuticals for effective and safe pain management. Current pharmacotherapy offers unsatisfactory solutions due to serious side effects related to the chronic use of opioid drugs. Prescription opioids produce analgesia through activation of the mu-opioid receptor (MOR) and are major contributors to the current opioid crisis. Multifunctional ligands possessing activity at more than one receptor represent a prominent therapeutic approach for the treatment of pain with fewer adverse effects. We recently reported on the design of a bifunctional MOR agonist/neuropeptide FF receptor (NPFFR) antagonist peptididomimetic, KGFF09 (H-Dmt-DArg-Aba-βAla-Bpa-Phe-NH₂), and its antinociceptive effects after subcutaneous (s.c.) administration in acute and persistent pain in mice with reduced propensity for unwanted side effects. In this study, we further investigated the antinociceptive properties of KGFF09 in a mouse model of visceral pain after s.c. administration and the potential for opioid-related liabilities of rewarding and sedation/locomotor dysfunction following chronic treatment. KGFF09 produced a significant dose-dependent inhibition of the writhing behavior in the acetic acid-induced writhing assay with increased potency when compared to morphine. We also demonstrated the absence of harmful effects caused by typical MOR agonists, i.e., rewarding effects (conditioned-place preference test) and sedation/locomotor impairment (open-field test), at a dose shown to be highly effective in inhibiting pain behavior. Consequently, KGFF09 displayed a favorable benefit/side effect ratio regarding these opioid-related side effects compared to conventional opioid analgesics, such as morphine, underlining the development of dual MOR agonists/NPFFR antagonists as improved treatments for various pain conditions. Full article

(This article belongs to the Special Issue Synthesis and Application of Opioids)

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12 pages, 1776 KiB

Open AccessArticle

Effects of Different Opioid Drugs on Oxidative Status and Proteasome Activity in SH-SY5Y Cells

by Laura Rullo, Francesca Felicia Caputi, Loredana Maria Losapio, Camilla Morosini, Luca Posa, Donatella Canistro, Fabio Vivarelli, Patrizia Romualdi and Sanzio Candeletti

Molecules 2022, 27(23), 8321; https://doi.org/10.3390/molecules27238321 - 29 Nov 2022

Cited by 3 | Viewed by 1383

Abstract

Opioids are the most effective drugs used for the management of moderate to severe pain; however, their chronic use is often associated with numerous adverse effects. Some results indicate the involvement of oxidative stress as well as of proteasome function in the development of some opioid-related side effects including analgesic tolerance, opioid-induced hyperalgesia (OIH) and dependence. Based on the evidence, this study investigated the impact of morphine, buprenorphine or tapentadol on intracellular reactive oxygen species levels (ROS), superoxide dismutase activity/gene expression, as well as β2 and β5 subunit proteasome activity/biosynthesis in SH-SY5Y cells. Results showed that tested opioids differently altered ROS production and SOD activity/biosynthesis. Indeed, the increase in ROS production and the reduction in SOD function elicited by morphine were not shared by the other opioids. Moreover, tested drugs produced distinct changes in β2(trypsin-like) and β5(chymotrypsin-like) proteasome activity and biosynthesis. In fact, while prolonged morphine exposure significantly increased the proteolytic activity of both subunits and β5 mRNA levels, buprenorphine and tapentadol either reduced or did not alter these parameters. These results, showing different actions of the selected opioid drugs on the investigated parameters, suggest that a low µ receptor intrinsic efficacy could be related to a smaller oxidative stress and proteasome activation and could be useful to shed more light on the role of the investigated cellular processes in the occurrence of these opioid drug side effects. Full article

(This article belongs to the Special Issue Synthesis and Application of Opioids)

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14 pages, 1724 KiB

Open AccessFeature PaperArticle

Evaluation of the Intracellular Signaling Activities of κ-Opioid Receptor Agonists, Nalfurafine Analogs; Focusing on the Selectivity of G-Protein- and β-Arrestin-Mediated Pathways

by Masahiro Yamaguchi, Kanako Miyano, Shigeto Hirayama, Yusuke Karasawa, Kaori Ohshima, Eiko Uezono, Akane Komatsu, Miki Nonaka, Hideaki Fujii, Keisuke Yamaguchi, Masako Iseki, Masakazu Hayashida and Yasuhito Uezono

Molecules 2022, 27(20), 7065; https://doi.org/10.3390/molecules27207065 - 19 Oct 2022

Cited by 2 | Viewed by 1699

Abstract

Opioid receptors (ORs) are classified into three types (μ, δ, and κ), and opioid analgesics are mainly mediated by μOR activation; however, their use is sometimes restricted by unfavorable effects. The selective κOR agonist nalfurafine was initially developed as an analgesic, but its indication was changed because of the narrow safety margin. The activation of ORs mainly induces two intracellular signaling pathways: a G-protein-mediated pathway and a β-arrestin-mediated pathway. Recently, the expectations for κOR analgesics that selectively activate these pathways have increased; however, the structural properties required for the selectivity of nalfurafine are still unknown. Therefore, we evaluated the partial structures of nalfurafine that are necessary for the selectivity of these two pathways. We assayed the properties of nalfurafine and six nalfurafine analogs (SYKs) using cells stably expressing κORs. The SYKs activated κORs in a concentration-dependent manner with higher EC₅₀ values than nalfurafine. Upon bias factor assessment, only SYK-309 (possessing the 3S-hydroxy group) showed higher selectivity of G-protein-mediated signaling activities than nalfurafine, suggesting the direction of the 3S-hydroxy group may affect the β-arrestin-mediated pathway. In conclusion, nalfurafine analogs having a 3S-hydroxy group, such as SYK-309, could be considered G-protein-biased κOR agonists. Full article

(This article belongs to the Special Issue Synthesis and Application of Opioids)

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15 pages, 1595 KiB

Open AccessArticle

Novel N-normetazocine Derivatives with Opioid Agonist/Sigma-1 Receptor Antagonist Profile as Potential Analgesics in Inflammatory Pain

by Rita Turnaturi, Santina Chiechio, Lorella Pasquinucci, Salvatore Spoto, Giuliana Costanzo, Maria Dichiara, Silvia Piana, Margherita Grasso, Emanuele Amata, Agostino Marrazzo and Carmela Parenti

Molecules 2022, 27(16), 5135; https://doi.org/10.3390/molecules27165135 - 12 Aug 2022

Cited by 7 | Viewed by 1540

Abstract

Although opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common drugs used in persistent pain treatment; they have shown many side effects. The development of new analgesics endowed with mu opioid receptor/delta opioid receptor (MOR/DOR) activity represents a promising alternative to MOR-selective compounds. Moreover, new mechanisms, such as sigma-1 receptor (σ₁R) antagonism, could be an opioid adjuvant strategy. The in vitro σ₁R and σ₂R profiles of previous synthesized MOR/DOR agonists (−)-2R/S-LP2 (1), (−)-2R-LP2 (2), and (−)-2S-LP2 (3) were assayed. To investigate the pivotal role of N-normetazocine stereochemistry, we also synthesized the (+)-2R/S-LP2 (7), (+)-2R-LP2 (8), and (+)-2S-LP2 (9) compounds. (−)-2R/S-LP2 (1), (−)-2R-LP2 (2), and (−)-2S-LP2 (3) compounds have Ki values for σ1R ranging between 112.72 and 182.81 nM, showing a multitarget opioid/σ1R profile. Instead, (+)-2R/S-LP2 (7), (+)-2R-LP2 (8), and (+)-2S-LP2 (9) isomers displayed a nanomolar affinity for σ1R, with significative selectivity vs. σ2R and opioid receptors. All isomers were evaluated using an in vivo formalin test. (−)-2S-LP2, at 0.7 mg/kg i.p., showed a significative and naloxone-reversed analgesic effect. The σ1R selective compound (+)-2R/S-LP2 (7), at 5.0 mg/kg i.p., decreased the second phase of the formalin test, showing an antagonist σ1R profile. The multitarget or single target profile of assayed N-normetazocine derivatives could represent a promising pharmacological strategy to enhance opioid potency and/or increase the safety margin. Full article

(This article belongs to the Special Issue Synthesis and Application of Opioids)

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21 pages, 7682 KiB

Open AccessArticle

Computational Methods for Understanding the Selectivity and Signal Transduction Mechanism of Aminomethyl Tetrahydronaphthalene to Opioid Receptors

by Peng Xie, Junjie Zhang, Baiyu Chen, Xinwei Li, Wenbo Zhang, Mengdan Zhu, Wei Li, Jianqi Li and Wei Fu

Molecules 2022, 27(7), 2173; https://doi.org/10.3390/molecules27072173 - 28 Mar 2022

Viewed by 1891

Abstract

Opioid receptors are members of the group of G protein-couple receptors, which have been proven to be effective targets for treating severe pain. The interactions between the opioid receptors and corresponding ligands and the receptor’s activation by different agonists have been among the most important fields in opioid research. In this study, with compound M1, an active metabolite of tramadol, as the clue compound, several aminomethyl tetrahydronaphthalenes were designed, synthesized and assayed upon opioid receptors. With the resultant compounds FW-AII-OH-1 (Ki = 141.2 nM for the κ opioid receptor), FW-AII-OH-2 (Ki = 4.64 nM for the δ opioid receptor), FW-DI-OH-2 (Ki = 8.65 nM for the δ opioid receptor) and FW-DIII-OH-2 (Ki = 228.45 nM for the δ opioid receptor) as probe molecules, the structural determinants responsible for the subtype selectivity and activation mechanisms were further investigated by molecular modeling and molecular dynamics simulations. It was shown that Y^7.43 was a key residue in determining the selectivity of the three opioid receptors, and W^6.58 was essential for the selectivity of the δ opioid receptor. A detailed stepwise discovered agonist-induced signal transduction mechanism of three opioid receptors by aminomethyl tetrahydronaphthalene compounds was proposed: the 3–7 lock between TM3 and TM7, the DRG lock between TM3 and TM6 and rearrangement of I^3.40, P^5.50 and F^6.44, which resulted in the cooperative movement in 7 TMs. Then, the structural relaxation left room for the binding of the G protein at the intracellular site, and finally the opioid receptors were activated. Full article

(This article belongs to the Special Issue Synthesis and Application of Opioids)

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Review

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25 pages, 1647 KiB

Open AccessReview

Insights into the Current and Possible Future Use of Opioid Antagonists in Relation to Opioid-Induced Constipation and Dysbiosis

by Nariman Essmat, Dávid Árpád Karádi, Ferenc Zádor, Kornél Király, Susanna Fürst and Mahmoud Al-Khrasani

Molecules 2023, 28(23), 7766; https://doi.org/10.3390/molecules28237766 - 24 Nov 2023

Cited by 3 | Viewed by 1620

Abstract

Opioid receptor agonists, particularly those that activate µ-opioid receptors (MORs), are essential analgesic agents for acute or chronic mild to severe pain treatment. However, their use has raised concerns including, among others, intestinal dysbiosis. In addition, growing data on constipation-evoked intestinal dysbiosis have been reported. Opioid-induced constipation (OIC) creates an obstacle to continuing treatment with opioid analgesics. When non-opioid therapies fail to overcome the OIC, opioid antagonists with peripheral, fast first-pass metabolism, and gastrointestinal localized effects remain the drug of choice for OIC, which are discussed here. At first glance, their use seems to only be restricted to constipation, however, recent data on OIC-related dysbiosis and its contribution to the appearance of several opioid side effects has garnered a great of attention from researchers. Peripheral MORs have also been considered as a future target for opioid analgesics with limited central side effects. The properties of MOR antagonists counteracting OIC, and with limited influence on central and possibly peripheral MOR-mediated antinociception, will be highlighted. A new concept is also proposed for developing gut-selective MOR antagonists to treat or restore OIC while keeping peripheral antinociception unaffected. The impact of opioid antagonists on OIC in relation to changes in the gut microbiome is included. Full article

(This article belongs to the Special Issue Synthesis and Application of Opioids)

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22 pages, 3442 KiB

Open AccessReview

Design of κ-Opioid Receptor Agonists for the Development of Potential Treatments of Pain with Reduced Side Effects

by Federica Santino and Luca Gentilucci

Molecules 2023, 28(1), 346; https://doi.org/10.3390/molecules28010346 - 1 Jan 2023

Cited by 7 | Viewed by 3915

Abstract

The κ-opioid receptor (KOR) has recently emerged as an alternative therapeutic target for the development of pain medications, without deleterious side effects associated with the μ-opioid receptor (MOR). However, modulation of KOR is currently under investigation for the treatment of depression, mood disorders, psychiatric comorbidity, and specific drug addictions. However, KOR agonists also trigger adverse effects including sedation, dysphoria, and hallucinations. In this respect, there is currently much debate on alternative paradigms. Recent effort has been devoted in search of biased ligands capable of selectively activating favorable signaling over signaling associated with unwanted side effects. On the other hand, the use of partial agonists is expected to allow the analgesia to be produced at dosages lower than those required to produce the adverse effects. More empirically, the unwanted central effects can be also avoided by using peripherally restricted agonists. In this review, we discuss the more recent trends in the design of KOR-selective, biased or partial, and finally, peripherally acting agonists. Special emphasis is given on the discussion of the most recent approaches for controlling functional selectivity of KOR-specific ligands. Full article

(This article belongs to the Special Issue Synthesis and Application of Opioids)

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13 pages, 1327 KiB

Open AccessReview

Ligand-Free Signaling of G-Protein-Coupled Receptors: Relevance to μ Opioid Receptors in Analgesia and Addiction

by Wolfgang Sadee and John C. McKew

Molecules 2022, 27(18), 5826; https://doi.org/10.3390/molecules27185826 - 8 Sep 2022

Cited by 1 | Viewed by 2229

Abstract

Numerous G-protein-coupled receptors (GPCRs) display ligand-free basal signaling with potential physiological functions, a target in drug development. As an example, the μ opioid receptor (MOR) signals in ligand-free form (MOR-μ*), influencing opioid responses. In addition, agonists bind to MOR but can dissociate upon MOR activation, with ligand-free MOR-μ* carrying out signaling. Opioid pain therapy is effective but incurs adverse effects (ADRs) and risk of opioid use disorder (OUD). Sustained opioid agonist exposure increases persistent basal MOR-μ* activity, which could be a driving force for OUD and ADRs. Antagonists competitively prevent resting MOR (MOR-μ) activation to MOR-μ*, while common antagonists, such as naloxone and naltrexone, also bind to and block ligand-free MOR-μ*, acting as potent inverse agonists. A neutral antagonist, 6β-naltrexol (6BN), binds to but does not block MOR-μ*, preventing MOR-μ activation only competitively with reduced potency. We hypothesize that 6BN gradually accelerates MOR-μ* reversal to resting-state MOR-μ. Thus, 6BN potently prevents opioid dependence in rodents, at doses well below those blocking antinociception or causing withdrawal. Acting as a ‘retrograde addiction modulator’, 6BN could represent a novel class of therapeutics for OUD. Further studies need to address regulation of MOR-μ* and, more broadly, the physiological and pharmacological significance of ligand-free signaling in GPCRs. Full article

(This article belongs to the Special Issue Synthesis and Application of Opioids)

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