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5 pages, 187 KiB

Open AccessEditorial

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

by Mariana Spetea and Helmut Schmidhammer

Molecules 2020, 25(23), 5658; https://doi.org/10.3390/molecules25235658 - 1 Dec 2020

Cited by 6 | Viewed by 2834

Abstract

The interest in opioids such as morphine, the prototypical opioid ligand, has been maintained throughout the years [...] Full article

(This article belongs to the Special Issue Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

Research

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16 pages, 9851 KiB

Open AccessArticle

Molecular Modeling of µ Opioid Receptor Ligands with Various Functional Properties: PZM21, SR-17018, Morphine, and Fentanyl—Simulated Interaction Patterns Confronted with Experimental Data

by Sabina Podlewska, Ryszard Bugno, Lucja Kudla, Andrzej J. Bojarski and Ryszard Przewlocki

Molecules 2020, 25(20), 4636; https://doi.org/10.3390/molecules25204636 - 12 Oct 2020

Cited by 22 | Viewed by 3731

Abstract

Molecular modeling approaches are an indispensable part of the drug design process. They not only support the process of searching for new ligands of a given receptor, but they also play an important role in explaining particular activity pathways of a compound. In [...] Read more.

Molecular modeling approaches are an indispensable part of the drug design process. They not only support the process of searching for new ligands of a given receptor, but they also play an important role in explaining particular activity pathways of a compound. In this study, a comprehensive molecular modeling protocol was developed to explain the observed activity profiles of selected µ opioid receptor agents: two G protein-biased µ opioid receptor agonists (PZM21 and SR-17018), unbiased morphine, and the β-arrestin-2-biased agonist, fentanyl. The study involved docking and molecular dynamics simulations carried out for three crystal structures of the target at a microsecond scale, followed by the statistical analysis of ligand–protein contacts. The interaction frequency between the modeled compounds and the subsequent residues of a protein during the simulation was also correlated with the output of in vitro and in vivo tests, resulting in the set of amino acids with the highest Pearson correlation coefficient values. Such indicated positions may serve as a guide for designing new G protein-biased ligands of the µ opioid receptor. Full article

(This article belongs to the Special Issue Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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14 pages, 4043 KiB

Open AccessArticle

Heteromerization of Endogenous Mu and Delta Opioid Receptors Induces Ligand-Selective Co-Targeting to Lysosomes

by Lyes Derouiche, Florian Pierre, Stéphane Doridot, Stéphane Ory and Dominique Massotte

Molecules 2020, 25(19), 4493; https://doi.org/10.3390/molecules25194493 - 30 Sep 2020

Cited by 13 | Viewed by 3168

Abstract

Increasing evidence indicates that native mu and delta opioid receptors can associate to form heteromers in discrete brain neuronal circuits. However, little is known about their signaling and trafficking. Using double-fluorescent knock-in mice, we investigated the impact of neuronal co-expression on the internalization [...] Read more.

Increasing evidence indicates that native mu and delta opioid receptors can associate to form heteromers in discrete brain neuronal circuits. However, little is known about their signaling and trafficking. Using double-fluorescent knock-in mice, we investigated the impact of neuronal co-expression on the internalization profile of mu and delta opioid receptors in primary hippocampal cultures. We established ligand selective mu–delta co-internalization upon activation by 1-[[4-(acetylamino)phenyl]methyl]-4-(2-phenylethyl)-4-piperidinecarboxylic acid, ethyl ester (CYM51010), [d-Ala2, NMe-Phe4, Gly-ol5]enkephalin (DAMGO), and deltorphin II, but not (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80), morphine, or methadone. Co-internalization was driven by the delta opioid receptor, required an active conformation of both receptors, and led to sorting to the lysosomal compartment. Altogether, our data indicate that mu–delta co-expression, likely through heteromerization, alters the intracellular fate of the mu opioid receptor, which provides a way to fine-tune mu opioid receptor signaling. It also represents an interesting emerging concept for the development of novel therapeutic drugs and strategies. Full article

(This article belongs to the Special Issue Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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20 pages, 3871 KiB

Open AccessArticle

Phenylalanine Stereoisomers of CJ-15,208 and [d-Trp]CJ-15,208 Exhibit Distinctly Different Opioid Activity Profiles

by Ariana C. Brice-Tutt, Sanjeewa N. Senadheera, Michelle L. Ganno, Shainnel O. Eans, Tanvir Khaliq, Thomas F. Murray, Jay P. McLaughlin and Jane V. Aldrich

Molecules 2020, 25(17), 3999; https://doi.org/10.3390/molecules25173999 - 2 Sep 2020

Cited by 12 | Viewed by 5350

Abstract

The macrocyclic tetrapeptide cyclo[Phe-d-Pro-Phe-Trp] (CJ-15,208) and its stereoisomer cyclo[Phe-d-Pro-Phe-d-Trp] exhibit different opioid activity profiles in vivo. The present study evaluated the influence of the Phe residues’ stereochemistry on the peptides’ opioid activity. Five stereoisomers were [...] Read more.

The macrocyclic tetrapeptide cyclo[Phe-d-Pro-Phe-Trp] (CJ-15,208) and its stereoisomer cyclo[Phe-d-Pro-Phe-d-Trp] exhibit different opioid activity profiles in vivo. The present study evaluated the influence of the Phe residues’ stereochemistry on the peptides’ opioid activity. Five stereoisomers were synthesized by a combination of solid-phase peptide synthesis and cyclization in solution. The analogs were evaluated in vitro for opioid receptor affinity in radioligand competition binding assays, and for opioid activity and selectivity in vivo in the mouse 55 °C warm-water tail-withdrawal assay. Potential liabilities of locomotor impairment, respiratory depression, acute tolerance development, and place conditioning were also assessed in vivo. All of the stereoisomers exhibited antinociception following either intracerebroventricular or oral administration differentially mediated by multiple opioid receptors, with kappa opioid receptor (KOR) activity contributing for all of the peptides. However, unlike the parent peptides, KOR antagonism was exhibited by only one stereoisomer, while another isomer produced DOR antagonism. The stereoisomers of CJ-15,208 lacked significant respiratory effects, while the [d-Trp]CJ-15,208 stereoisomers did not elicit antinociceptive tolerance. Two isomers, cyclo[d-Phe-d-Pro-d-Phe-Trp] (3) and cyclo[Phe-d-Pro-d-Phe-d-Trp] (5), did not elicit either preference or aversion in a conditioned place preference assay. Collectively, these stereoisomers represent new lead compounds for further investigation in the development of safer opioid analgesics. Full article

(This article belongs to the Special Issue Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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25 pages, 5212 KiB

Open AccessArticle

Zerumbone-Induced Analgesia Modulated via Potassium Channels and Opioid Receptors in Chronic Constriction Injury-Induced Neuropathic Pain

by Banulata Gopalsamy, Jasmine Siew Min Chia, Ahmad Akira Omar Farouk, Mohd Roslan Sulaiman and Enoch Kumar Perimal

Molecules 2020, 25(17), 3880; https://doi.org/10.3390/molecules25173880 - 26 Aug 2020

Cited by 13 | Viewed by 3050

Abstract

Zerumbone, a monocyclic sesquiterpene from the wild ginger plant Zingiber zerumbet (L.) Smith, attenuates allodynia and hyperalgesia. Currently, its mechanisms of action in neuropathic pain conditions remain unclear. This study examines the involvement of potassium channels and opioid receptors in zerumbone-induced analgesia in [...] Read more.

Zerumbone, a monocyclic sesquiterpene from the wild ginger plant Zingiber zerumbet (L.) Smith, attenuates allodynia and hyperalgesia. Currently, its mechanisms of action in neuropathic pain conditions remain unclear. This study examines the involvement of potassium channels and opioid receptors in zerumbone-induced analgesia in a chronic constriction injury (CCI) neuropathic pain mice model. Male Institute of Cancer Research (ICR) mice were subjected to CCI and behavioral responses were tested on day 14. Responses toward mechanical allodynia and thermal hyperalgesia were tested with von Frey’s filament and Hargreaves’ tests, respectively. Symptoms of neuropathic pain were significantly alleviated following treatment with zerumbone (10 mg/kg; intraperitoneal, i.p.). However, when the voltage-dependent K⁺ channel blocker tetraethylammonium (TEA, 4 mg/kg; i.p.), ATP-sensitive K⁺ channel blocker, glibenclamide (GLIB, 10 mg/kg; i.p.); small-conductance Ca²⁺-activated K⁺ channel inhibitor apamin (APA, 0.04 mg/kg; i.p.), or large-conductance Ca²⁺-activated K⁺ channel inhibitor charybdotoxin (CHAR, 0.02 mg/kg; i.p.) was administered prior to zerumbone (10 mg/kg; i.p.), the antiallodynic and antihyperalgesic effects of zerumbone were significantly reversed. Additionally, non-specific opioid receptors antagonist, naloxone (NAL, 10 mg/kg; i.p.), selective µ-, δ- and κ-opioid receptor antagonists; β-funaltrexamine (β-FN, 40 mg/kg; i.p.), naltrindole (20 mg/kg; s.c.), nor-binaltorphamine (10 mg/kg; s.c.) respectively attenuated the antiallodynic and antihyperalgesic effects of zerumbone. This outcome clearly demonstrates the participation of potassium channels and opioid receptors in the antineuropathic properties of zerumbone. As various clinically used neuropathic pain drugs also share this similar mechanism, this compound is, therefore, a highly potential substitute to these therapeutic options. Full article

(This article belongs to the Special Issue Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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17 pages, 1304 KiB

Open AccessArticle

Effects of N-Substituents on the Functional Activities of Naltrindole Derivatives for the δ Opioid Receptor: Synthesis and Evaluation of Sulfonamide Derivatives

by Chiharu Iwamatsu, Daichi Hayakawa, Tomomi Kono, Ayaka Honjo, Saki Ishizaki, Shigeto Hirayama, Hiroaki Gouda and Hideaki Fujii

Molecules 2020, 25(17), 3792; https://doi.org/10.3390/molecules25173792 - 20 Aug 2020

Cited by 6 | Viewed by 2784

Abstract

We have recently reported that N-alkyl and N-acyl naltrindole (NTI) derivatives showed activities for the δ opioid receptor (DOR) ranging widely from full inverse agonists to full agonists. We newly designed sulfonamide-type NTI derivatives in order to investigate the effects of [...] Read more.

We have recently reported that N-alkyl and N-acyl naltrindole (NTI) derivatives showed activities for the δ opioid receptor (DOR) ranging widely from full inverse agonists to full agonists. We newly designed sulfonamide-type NTI derivatives in order to investigate the effects of the N-substituent on the functional activities because the side chain and S=O part in the sulfonamide moiety located in spatially different positions compared with those in the alkylamine and amide moieties. Among the tested compounds, cyclopropylsulfonamide 9f (SYK-839) was the most potent full inverse agonist for the DOR, whereas phenethylsulfonamide 9e (SYK-901) showed full DOR agonist activity with moderate potency. These NTI derivatives are expected to be useful compounds for investigation of the molecular mechanism inducing these functional activities. Full article

(This article belongs to the Special Issue Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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32 pages, 5924 KiB

Open AccessArticle

The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of “Tail Wags Dog” Experiments

by Meining Wang, Thomas C. Irvin, Christine A. Herdman, Ramsey D. Hanna, Sergio A. Hassan, Yong-Sok Lee, Sophia Kaska, Rachel Saylor Crowley, Thomas E. Prisinzano, Sarah L. Withey, Carol A. Paronis, Jack Bergman, Saadet Inan, Ellen B. Geller, Martin W. Adler, Theresa A. Kopajtic, Jonathan L. Katz, Aaron M. Chadderdon, John R. Traynor, Arthur E. Jacobson and Kenner C. Rice Show full author list Hide full author list

Molecules 2020, 25(11), 2640; https://doi.org/10.3390/molecules25112640 - 6 Jun 2020

Cited by 11 | Viewed by 4241

Abstract

(−)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [³⁵S]GTPγS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated β-arrestin recruitment assays). “Body” and “tail” interactions with opioid [...] Read more.

(−)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [³⁵S]GTPγS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated β-arrestin recruitment assays). “Body” and “tail” interactions with opioid receptors (a subset of Portoghese’s message-address theory) were used for molecular modeling and simulations, where the “address” can be considered the “body” of the hydromorphone molecule and the “message” delivered by the substituent (tail) on the aromatic ring of the N-phenethyl moiety. One compound, N-p-chloro-phenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 2i), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a δ/μ potency ratio of 1.2 in the ([³⁵S]GTPγS) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer side-effects than MOR agonists. The p-chlorophenethyl compound 2i was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound 2i did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO₂), respiration was depressed in squirrel monkeys. Full article

(This article belongs to the Special Issue Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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18 pages, 3167 KiB

Open AccessArticle

β²-Homo-Amino Acid Scan of µ-Selective Opioid Tetrapeptide TAPP

by Dagmara Tymecka, Piotr F. J. Lipiński, Piotr Kosson and Aleksandra Misicka

Molecules 2020, 25(10), 2461; https://doi.org/10.3390/molecules25102461 - 25 May 2020

Cited by 6 | Viewed by 4007

Abstract

TAPP (H-Tyr-d-Ala-Phe-Phe-NH₂) is a potent, µ-selective opioid ligand. In order to gain further insights into pharmacophoric features of this tetrapeptide, we have performed a β²-Homo-amino acid (β²hAA) scan of the TAPP sequence. To [...] Read more.

TAPP (H-Tyr-d-Ala-Phe-Phe-NH₂) is a potent, µ-selective opioid ligand. In order to gain further insights into pharmacophoric features of this tetrapeptide, we have performed a β²-Homo-amino acid (β²hAA) scan of the TAPP sequence. To this aim, 10 novel analogues have been synthesized and evaluated for µ-opioid and δ-opioid receptor affinity as well as for stability in human plasma. The derivatives included compounds in which a (R)- or (S)-β²-Homo-Homologue replaced the amino acids in the TAPP sequence. The derivatives with (R)- or (S)-β²hPhe⁴ turned out to bind µOR with affinities equal to that of the parent. β²hAAs in position 1 and 3 resulted in rather large affinity decreases, but the change differed depending on the stereochemistry. β²-Homologation in the second position gave derivatives with very poor µOR binding. According to molecular modelling, the presented α/β-peptides adopt a variety of binding poses with their common element being an ionic interaction between a protonable amine of the first residue and Asp147. A feature required for high µOR affinity seems the ability to accommodate the ring in the fourth residue in a manner similar to that found for TAPP. Contrary to what might be expected, several compounds were significantly less stable in human plasma than the parent compound. Full article

(This article belongs to the Special Issue Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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12 pages, 4495 KiB

Open AccessArticle

Mechanistic Understanding of Peptide Analogues, DALDA, [Dmt¹]DALDA, and KGOP01, Binding to the Mu Opioid Receptor

by Maria Dumitrascuta, Marcel Bermudez, Steven Ballet, Gerhard Wolber and Mariana Spetea

Molecules 2020, 25(9), 2087; https://doi.org/10.3390/molecules25092087 - 29 Apr 2020

Cited by 15 | Viewed by 4396

Abstract

The mu opioid receptor (MOR) is the primary target for analgesia of endogenous opioid peptides, alkaloids, synthetic small molecules with diverse scaffolds, and peptidomimetics. Peptide-based opioids are viewed as potential analgesics with reduced side effects and have received constant scientific interest over the [...] Read more.

The mu opioid receptor (MOR) is the primary target for analgesia of endogenous opioid peptides, alkaloids, synthetic small molecules with diverse scaffolds, and peptidomimetics. Peptide-based opioids are viewed as potential analgesics with reduced side effects and have received constant scientific interest over the years. This study focuses on three potent peptide and peptidomimetic MOR agonists, DALDA, [Dmt¹]DALDA, and KGOP01, and the prototypical peptide MOR agonist DAMGO. We present the first molecular modeling study and structure–activity relationships aided by in vitro assays and molecular docking of the opioid peptide analogues, in order to gain insight into their mode of binding to the MOR. In vitro binding and functional assays revealed the same rank order with KGOP01 > [Dmt¹]DALDA > DAMGO > DALDA for both binding and MOR activation. Using molecular docking at the MOR and three-dimensional interaction pattern analysis, we have rationalized the experimental outcomes and highlighted key amino acid residues responsible for agonist binding to the MOR. The Dmt (2′,6′-dimethyl-L-Tyr) moiety of [Dmt¹]DALDA and KGOP01 was found to represent the driving force for their high potency and agonist activity at the MOR. These findings contribute to a deeper understanding of MOR function and flexible peptide ligand–MOR interactions, that are of significant relevance for the future design of opioid peptide-based analgesics. Full article

(This article belongs to the Special Issue Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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22 pages, 4001 KiB

Open AccessArticle

Comparisons of In Vivo and In Vitro Opioid Effects of Newly Synthesized 14-Methoxycodeine-6-O-sulfate and Codeine-6-O-sulfate

by Ferenc Zádor, Amir Mohammadzadeh, Mihály Balogh, Zoltán S. Zádori, Kornél Király, Szilvia Barsi, Anna Rita Galambos, Szilvia B. László, Barbara Hutka, András Váradi, Sándor Hosztafi, Pál Riba, Sándor Benyhe, Susanna Fürst and Mahmoud Al-Khrasani

Molecules 2020, 25(6), 1370; https://doi.org/10.3390/molecules25061370 - 17 Mar 2020

Cited by 11 | Viewed by 5439

Abstract

The present work represents the in vitro (potency, affinity, efficacy) and in vivo (antinociception, constipation) opioid pharmacology of the novel compound 14-methoxycodeine-6-O-sulfate (14-OMeC6SU), compared to the reference compounds codeine-6-O-sulfate (C6SU), codeine and morphine. Based on in vitro tests (mouse [...] Read more.

The present work represents the in vitro (potency, affinity, efficacy) and in vivo (antinociception, constipation) opioid pharmacology of the novel compound 14-methoxycodeine-6-O-sulfate (14-OMeC6SU), compared to the reference compounds codeine-6-O-sulfate (C6SU), codeine and morphine. Based on in vitro tests (mouse and rat vas deferens, receptor binding and [³⁵S]GTPγS activation assays), 14-OMeC6SU has µ-opioid receptor-mediated activity, displaying higher affinity, potency and efficacy than the parent compounds. In rats, 14-OMeC6SU showed stronger antinociceptive effect in the tail-flick assay than codeine and was equipotent to morphine, whereas C6SU was less efficacious after subcutaneous (s.c.) administration. Following intracerebroventricular injection, 14-OMeC6SU was more potent than morphine. In the Complete Freund’s Adjuvant-induced inflammatory hyperalgesia, 14-OMeC6SU and C6SU in s.c. doses up to 6.1 and 13.2 µmol/kg, respectively, showed peripheral antihyperalgesic effect, because co-administered naloxone methiodide, a peripherally acting opioid receptor antagonist antagonized the measured antihyperalgesia. In addition, s.c. C6SU showed less pronounced inhibitory effect on the gastrointestinal transit than 14-OMeC6SU, codeine and morphine. This study provides first evidence that 14-OMeC6SU is more effective than codeine or C6SU in vitro and in vivo. Furthermore, despite C6SU peripheral antihyperalgesic effects with less gastrointestinal side effects the superiority of 14-OMeC6SU was obvious throughout the present study. Full article

(This article belongs to the Special Issue Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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10 pages, 3944 KiB

Open AccessCommunication

Structure-Activity Relationship between Thiol Group-Trapping Ability of Morphinan Compounds with a Michael Acceptor and Anti-Plasmodium falciparum Activities

by Noriki Kutsumura, Yasuaki Koyama, Tsuyoshi Saitoh, Naoshi Yamamoto, Yasuyuki Nagumo, Yoshiyuki Miyata, Rei Hokari, Aki Ishiyama, Masato Iwatsuki, Kazuhiko Otoguro, Satoshi Ōmura and Hiroshi Nagase

Molecules 2020, 25(5), 1112; https://doi.org/10.3390/molecules25051112 - 2 Mar 2020

Cited by 3 | Viewed by 3654

Abstract

7-Benzylidenenaltrexone (BNTX) and most of its derivatives showed in vitro antimalarial activities against chloroquine-resistant and -sensitive Plasmodium falciparum strains (K1 and FCR3, respectively). In addition, the time-dependent changes of the addition reactions of the BNTX derivatives with 1-propanethiol were examined by ¹H-NMR [...] Read more.

7-Benzylidenenaltrexone (BNTX) and most of its derivatives showed in vitro antimalarial activities against chloroquine-resistant and -sensitive Plasmodium falciparum strains (K1 and FCR3, respectively). In addition, the time-dependent changes of the addition reactions of the BNTX derivatives with 1-propanethiol were examined by ¹H-NMR experiments to estimate their thiol group-trapping ability. The relative chemical reactivity of the BNTX derivatives to trap the thiol group of 1-propanethiol was correlated highly with the antimalarial activity. Therefore, the measurements of the thiol group-trapping ability of the BNTX derivatives with a Michael acceptor is expected to become an alternative method for in vitro malarial activity and related assays. Full article

(This article belongs to the Special Issue Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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15 pages, 1368 KiB

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

by Robert J. Cassell, Krishna K. Sharma, Hongyu Su, Benjamin R. Cummins, Haoyue Cui, Kendall L. Mores, Arryn T. Blaine, Ryan A. Altman and Richard M. van Rijn

Molecules 2019, 24(24), 4542; https://doi.org/10.3390/molecules24244542 - 12 Dec 2019

Cited by 9 | Viewed by 5616

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

(This article belongs to the Special Issue Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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14 pages, 2500 KiB

Open AccessArticle

Synthesis and Pharmacological Evaluation of Hybrids Targeting Opioid and Neurokinin Receptors

by Karol Wtorek, Anna Adamska-Bartłomiejczyk, Justyna Piekielna-Ciesielska, Federica Ferrari, Chiara Ruzza, Alicja Kluczyk, Joanna Piasecka-Zelga, Girolamo Calo’ and Anna Janecka

Molecules 2019, 24(24), 4460; https://doi.org/10.3390/molecules24244460 - 5 Dec 2019

Cited by 10 | Viewed by 3976

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

(This article belongs to the Special Issue Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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Review

Jump to: Editorial, Research

24 pages, 3938 KiB

Open AccessReview

Development of Diphenethylamines as Selective Kappa Opioid Receptor Ligands and Their Pharmacological Activities

by Helmut Schmidhammer, Filippo Erli, Elena Guerrieri and Mariana Spetea

Molecules 2020, 25(21), 5092; https://doi.org/10.3390/molecules25215092 - 2 Nov 2020

Cited by 10 | Viewed by 4019

Abstract

Among the opioid receptors, the kappa opioid receptor (KOR) has been gaining substantial attention as a promising molecular target for the treatment of numerous human disorders, including pain, pruritus, affective disorders (i.e., depression and anxiety), drug addiction, and neurological diseases (i.e., epilepsy). Particularly, [...] Read more.

Among the opioid receptors, the kappa opioid receptor (KOR) has been gaining substantial attention as a promising molecular target for the treatment of numerous human disorders, including pain, pruritus, affective disorders (i.e., depression and anxiety), drug addiction, and neurological diseases (i.e., epilepsy). Particularly, the knowledge that activation of the KOR, opposite to the mu opioid receptor (MOR), does not produce euphoria or leads to respiratory depression or overdose, has stimulated the interest in discovering ligands targeting the KOR as novel pharmacotherapeutics. However, the KOR mediates the negative side effects of dysphoria/aversion, sedation, and psychotomimesis, with the therapeutic promise of biased agonism (i.e., selective activation of beneficial over deleterious signaling pathways) for designing safer KOR therapeutics without the liabilities of conventional KOR agonists. In this review, the development of new KOR ligands from the class of diphenethylamines is presented. Specifically, we describe the design strategies, synthesis, and pharmacological activities of differently substituted diphenethylamines, where structure–activity relationships have been extensively studied. Ligands with distinct profiles as potent and selective agonists, G protein-biased agonists, and selective antagonists, and their potential use as therapeutic agents (i.e., pain treatment) and research tools are described. Full article

(This article belongs to the Special Issue Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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34 pages, 3287 KiB

Open AccessReview

Biased Opioid Ligands

by Abdelfattah Faouzi, Balazs R. Varga and Susruta Majumdar

Molecules 2020, 25(18), 4257; https://doi.org/10.3390/molecules25184257 - 16 Sep 2020

Cited by 89 | Viewed by 12464

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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14 pages, 1700 KiB

Open AccessReview

Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management

by Wolfgang Sadee, John Oberdick and Zaijie Wang

Molecules 2020, 25(18), 4163; https://doi.org/10.3390/molecules25184163 - 11 Sep 2020

Cited by 8 | Viewed by 4680

Abstract

Opioid analgesics are effective pain therapeutics but they cause various adverse effects and addiction. For safer pain therapy, biased opioid agonists selectively target distinct μ opioid receptor (MOR) conformations, while the potential of biased opioid antagonists has been neglected. Agonists convert a dormant [...] Read more.

Opioid analgesics are effective pain therapeutics but they cause various adverse effects and addiction. For safer pain therapy, biased opioid agonists selectively target distinct μ opioid receptor (MOR) conformations, while the potential of biased opioid antagonists has been neglected. Agonists convert a dormant receptor form (MOR-μ) to a ligand-free active form (MOR-μ*), which mediates MOR signaling. Moreover, MOR-μ converts spontaneously to MOR-μ* (basal signaling). Persistent upregulation of MOR-μ* has been invoked as a hallmark of opioid dependence. Contrasting interactions with both MOR-μ and MOR-μ* can account for distinct pharmacological characteristics of inverse agonists (naltrexone), neutral antagonists (6β-naltrexol), and mixed opioid agonist-antagonists (buprenorphine). Upon binding to MOR-μ*, naltrexone but not 6β-naltrexol suppresses MOR-μ*signaling. Naltrexone blocks opioid analgesia non-competitively at MOR-μ*with high potency, whereas 6β-naltrexol must compete with agonists at MOR-μ, accounting for ~100-fold lower in vivo potency. Buprenorphine’s bell-shaped dose–response curve may also result from opposing effects on MOR-μ and MOR-μ*. In contrast, we find that 6β-naltrexol potently prevents dependence, below doses affecting analgesia or causing withdrawal, possibly binding to MOR conformations relevant to opioid dependence. We propose that 6β-naltrexol is a biased opioid antagonist modulating opioid dependence at low doses, opening novel avenues for opioid pain therapy and use management. Full article

(This article belongs to the Special Issue Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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13 pages, 1171 KiB

Open AccessReview

Pharmacological Aspects of Over-the-Counter Opioid Drugs Misuse

by Łukasz Sobczak and Krzysztof Goryński

Molecules 2020, 25(17), 3905; https://doi.org/10.3390/molecules25173905 - 27 Aug 2020

Cited by 24 | Viewed by 8895

Abstract

Several over-the-counter (OTC) drugs are known to be misused. Among them are opioids such as codeine, dihydrocodeine, and loperamide. This work elucidates their pharmacology, interactions, safety profiles, and how pharmacology is being manipulated to misuse these common medications, with the aim to expand [...] Read more.

Several over-the-counter (OTC) drugs are known to be misused. Among them are opioids such as codeine, dihydrocodeine, and loperamide. This work elucidates their pharmacology, interactions, safety profiles, and how pharmacology is being manipulated to misuse these common medications, with the aim to expand on the subject outlined by the authors focusing on abuse prevention and prevalence rates. The reviewed literature was identified in several online databases through searches conducted with phrases created by combining the international non-proprietary names of the drugs with terms related to drug misuse. The results show that OTC opioids are misused as an alternative for illicit narcotics, or prescription-only opioids. The potency of codeine and loperamide is strongly dependent on the individual enzymatic activity of CYP2D6 and CYP3A4, as well as P-glycoprotein function. Codeine can also be utilized as a substrate for clandestine syntheses of more potent drugs of abuse, namely desomorphine (“Krokodil”), and morphine. The dangerous methods used to prepare these substances can result in poisoning from toxic chemicals and impurities originating from the synthesis procedure. OTC opioids are generally safe when consumed in accordance with medical guidelines. However, the intake of supratherapeutic amounts of these substances may reveal surprising traits of common medications. Full article

(This article belongs to the Special Issue Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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13 pages, 856 KiB

Open AccessReview

Biased versus Partial Agonism in the Search for Safer Opioid Analgesics

by Joaquim Azevedo Neto, Anna Costanzini, Roberto De Giorgio, David G. Lambert, Chiara Ruzza and Girolamo Calò

Molecules 2020, 25(17), 3870; https://doi.org/10.3390/molecules25173870 - 25 Aug 2020

Cited by 58 | Viewed by 6961

Abstract

Opioids such as morphine—acting at the mu opioid receptor—are the mainstay for treatment of moderate to severe pain and have good efficacy in these indications. However, these drugs produce a plethora of unwanted adverse effects including respiratory depression, constipation, immune suppression and with [...] Read more.

Opioids such as morphine—acting at the mu opioid receptor—are the mainstay for treatment of moderate to severe pain and have good efficacy in these indications. However, these drugs produce a plethora of unwanted adverse effects including respiratory depression, constipation, immune suppression and with prolonged treatment, tolerance, dependence and abuse liability. Studies in β-arrestin 2 gene knockout (βarr2(−/−)) animals indicate that morphine analgesia is potentiated while side effects are reduced, suggesting that drugs biased away from arrestin may manifest with a reduced-side-effect profile. However, there is controversy in this area with improvement of morphine-induced constipation and reduced respiratory effects in βarr2(−/−) mice. Moreover, studies performed with mice genetically engineered with G-protein-biased mu receptors suggested increased sensitivity of these animals to both analgesic actions and side effects of opioid drugs. Several new molecules have been identified as mu receptor G-protein-biased agonists, including oliceridine (TRV130), PZM21 and SR–17018. These compounds have provided preclinical data with apparent support for bias toward G proteins and the genetic premise of effective and safer analgesics. There are clinical data for oliceridine that have been very recently approved for short term intravenous use in hospitals and other controlled settings. While these data are compelling and provide a potential new pathway-based target for drug discovery, a simpler explanation for the behavior of these biased agonists revolves around differences in intrinsic activity. A highly detailed study comparing oliceridine, PZM21 and SR–17018 (among others) in a range of assays showed that these molecules behave as partial agonists. Moreover, there was a correlation between their therapeutic indices and their efficacies, but not their bias factors. If there is amplification of G-protein, but not arrestin pathways, then agonists with reduced efficacy would show high levels of activity at G-protein and low or absent activity at arrestin; offering analgesia with reduced side effects or ‘apparent bias’. Overall, the current data suggests—and we support—caution in ascribing biased agonism to reduced-side-effect profiles for mu-agonist analgesics. Full article

(This article belongs to the Special Issue Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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22 pages, 1311 KiB

Open AccessReview

On the Role of Peripheral Sensory and Gut Mu Opioid Receptors: Peripheral Analgesia and Tolerance

by Susanna Fürst, Zoltán S. Zádori, Ferenc Zádor, Kornél Király, Mihály Balogh, Szilvia B. László, Barbara Hutka, Amir Mohammadzadeh, Chiara Calabrese, Anna Rita Galambos, Pál Riba, Patrizia Romualdi, Sándor Benyhe, Júlia Timár, Helmut Schmidhammer, Mariana Spetea and Mahmoud Al-Khrasani

Molecules 2020, 25(11), 2473; https://doi.org/10.3390/molecules25112473 - 26 May 2020

Cited by 19 | Viewed by 5313

Abstract

There is growing evidence on the role of peripheral µ-opioid receptors (MORs) in analgesia and analgesic tolerance. Opioid analgesics are the mainstay in the management of moderate to severe pain, and their efficacy in the alleviation of pain is well recognized. Unfortunately, chronic [...] Read more.

There is growing evidence on the role of peripheral µ-opioid receptors (MORs) in analgesia and analgesic tolerance. Opioid analgesics are the mainstay in the management of moderate to severe pain, and their efficacy in the alleviation of pain is well recognized. Unfortunately, chronic treatment with opioid analgesics induces central analgesic tolerance, thus limiting their clinical usefulness. Numerous molecular mechanisms, including receptor desensitization, G-protein decoupling, β-arrestin recruitment, and alterations in the expression of peripheral MORs and microbiota have been postulated to contribute to the development of opioid analgesic tolerance. However, these studies are largely focused on central opioid analgesia and tolerance. Accumulated literature supports that peripheral MORs mediate analgesia, but controversial results on the development of peripheral opioid receptors-mediated analgesic tolerance are reported. In this review, we offer evidence on the consequence of the activation of peripheral MORs in analgesia and analgesic tolerance, as well as approaches that enhance analgesic efficacy and decrease the development of tolerance to opioids at the peripheral sites. We have also addressed the advantages and drawbacks of the activation of peripheral MORs on the sensory neurons and gut (leading to dysbiosis) on the development of central and peripheral analgesic tolerance. Full article

(This article belongs to the Special Issue Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery)

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