A Bifunctional Biased Mu Opioid Agonist - Neuropeptide Ff Receptor Antagonist as Analgesic with Improved Acute and Chronic Side Effects

Rochelle, Armand Drieu la; Guillemyn, Karel; Dumitrascuta, Maria; González, Simón; Martin, Charlotte; Utard, Valérie; Quillet, Raphaëlle; Schneider, Séverine; Daubeuf, François; Willemse, Tom; Mampuys, Pieter; Maes, Bert U. W.; Frossard, Nelly; Bihel, Frédéric; Spetea, Mariana; Simonin, Frédéric; Ballet, Steven

doi:10.17952/35eps.2018.276

Cited by 3 publications

(5 citation statements)

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“…It could, therefore, be suggested that the impact of NK2 and NK3 pharmacophores on opioid activity will strongly depend on the nature of the opioid pharmacophore. The data suggest that anchorage of any C -terminal appendage to the constrained structure of KGOP01 is more tolerated, which is in line with previous studies [ 19 , 38 , 39 ]. In light of the promising opioid data, the KGOP01-based hybrids were therefore selected for further biological evaluation, and NK2 and NK3 receptor binding assays were performed.…”

Section: Discussionsupporting

confidence: 91%

Harnessing the Anti-Nociceptive Potential of NK2 and NK3 Ligands in the Design of New Multifunctional μ/δ-Opioid Agonist–Neurokinin Antagonist Peptidomimetics

et al. 2021

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Opioid agonists are well-established analgesics, widely prescribed for acute but also chronic pain. However, their efficiency comes with the price of drastically impacting side effects that are inherently linked to their prolonged use. To answer these liabilities, designed multiple ligands (DMLs) offer a promising strategy by co-targeting opioid and non-opioid signaling pathways involved in nociception. Despite being intimately linked to the Substance P (SP)/neurokinin 1 (NK1) system, which is broadly examined for pain treatment, the neurokinin receptors NK2 and NK3 have so far been neglected in such DMLs. Herein, a series of newly designed opioid agonist-NK2 or -NK3 antagonists is reported. A selection of reported peptidic, pseudo-peptidic, and non-peptide neurokinin NK2 and NK3 ligands were covalently linked to the peptidic μ-opioid selective pharmacophore Dmt-DALDA (H-Dmt-d-Arg-Phe-Lys-NH2) and the dual μ/δ opioid agonist H-Dmt-d-Arg-Aba-βAla-NH2 (KGOP01). Opioid binding assays unequivocally demonstrated that only hybrids SBL-OPNK-5, SBL-OPNK-7 and SBL-OPNK-9, bearing the KGOP01 scaffold, conserved nanomolar range μ-opioid receptor (MOR) affinity, and slightly reduced affinity for the δ-opioid receptor (DOR). Moreover, NK binding experiments proved that compounds SBL-OPNK-5, SBL-OPNK-7, and SBL-OPNK-9 exhibited (sub)nanomolar binding affinity for NK2 and NK3, opening promising opportunities for the design of next-generation opioid hybrids.

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Section: Discussionsupporting

confidence: 91%

Harnessing the Anti-Nociceptive Potential of NK2 and NK3 Ligands in the Design of New Multifunctional μ/δ-Opioid Agonist–Neurokinin Antagonist Peptidomimetics

et al. 2021

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“…DALDA, [Dmt 1 ]DALDA, and KGOP01 have high stability against enzymatic degradation, due to the presence of certain structural modifications, i.e., unnatural and synthetic amino acids. While DALDA does not cross the BBB, the [Dmt 1 ]DALDA and KGOP01 can enter the CNS [13,42]. The gained knowledge from this study on which molecular interactions with the MOR these opioid peptides share and distinguish them, with Y148 3.33 and Y326 7.42 sites being of significance, may also help to understand the differences in the pharmacokinetics between these peptides.…”

Section: Discussionmentioning

confidence: 84%

“…Further, an enhanced MOR agonist potency by 5-fold was measured in the present study for KGOP01 as compared to [Dmt 1 ]DALDA in the [ 35 S]GTPγS binding assay (Table 1). The potent MOR agonist profile of KGOP01 was established previously in the GPI bioassay (IC 50 = 0.8 nM) [34] and cAMP accumulation assay with HEK293 cells expressing the human MOR (EC 50 = 0.204 nM) [42]. The outcomes derived from functional assays correlate well with the results obtained in binding studies at the MOR and structural features of investigated peptide analogues, where [Dmt 1 ]DALDA and KGOP01 show a better in vitro profile than DALDA, with KGOP01 being the most potent MOR agonist of the series.…”

Section: Comparison Of In Vitro Binding and Activation Profiles Of Dalda [Dmt 1 ]Dalda And Kgop01 To The Mormentioning

confidence: 99%

“…Over the years, the MOR received a constant attention as the most important opioid receptor subtype responsible for opioid-induced analgesia, but concomitantly is also most responsible for the unwanted side effects (e.g., respiratory depression, constipation, sedation, dependence, and tolerance) of opioid stable analogue of [Dmt 1 ]DALDA with two unnatural amino acids, 4-amino-tetrahydro-2-benzazepinone (Aba) at position 3 and βAla at position 4 [34]. The rationale for the selection of these peptide analogues is based on the numerous in vitro and in vivo studies that have established them as stable, potent MOR agonists and effective analgesics in animal pain models with an interesting pharmacology, as well as based on their value as leads in the development of new peptide ligands [13,[34][35][36][37][38][39][40][41][42][43]. However, binding behavior of DALDA, [Dmt 1 ]DALDA, and KGOP01 to their primary target, the MOR, using computational approaches has not been investigated up to now.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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“…KGFF03 and KGFF09 are hybrid compounds. Both of them were described as G protein-biased μ-OR agonists, but KGFF03 presented full agonistic and KGFF09 full antagonistic activity at neuropeptide FF receptor [ 81 ]. Chronic treatment with KGFF09 did not result in the development of tolerance and induced less physical dependence than control substances, indicating that bifunctional compounds constitute an interesting strategy to develop opioids with reduced addictive properties.…”

Section: Addictive Properties Of G Protein-biased μ-Or Agonistsmentioning

confidence: 99%

Influence of G protein-biased agonists of μ-opioid receptor on addiction-related behaviors

Kudla

Przewłocki

2021

Pharmacol. Rep

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Opioid analgesics remain a gold standard for the treatment of moderate to severe pain. However, their clinical utility is seriously limited by a range of adverse effects. Among them, their high-addictive potential appears as very important, especially in the context of the opioid epidemic. Therefore, the development of safer opioid analgesics with low abuse potential appears as a challenging problem for opioid research. Among the last few decades, different approaches to the discovery of novel opioid drugs have been assessed. One of the most promising is the development of G protein-biased opioid agonists, which can activate only selected intracellular signaling pathways. To date, discoveries of several biased agonists acting via μ-opioid receptor were reported. According to the experimental data, such ligands may be devoid of at least some of the opioid side effects, such as respiratory depression or constipation. Nevertheless, most data regarding the addictive properties of biased μ-opioid receptor agonists are inconsistent. A global problem connected with opioid abuse also requires the search for effective pharmacotherapy for opioid addiction, which is another potential application of biased compounds. This review discusses the state-of-the-art on addictive properties of G protein-biased μ-opioid receptor agonists as well as we analyze whether these compounds can diminish any symptoms of opioid addiction. Finally, we provide a critical view on recent data connected with biased signaling and its implications to in vivo manifestations of addiction. Graphic abstract

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A Bifunctional Biased Mu Opioid Agonist - Neuropeptide Ff Receptor Antagonist as Analgesic with Improved Acute and Chronic Side Effects

Cited by 3 publications

References 5 publications

Harnessing the Anti-Nociceptive Potential of NK2 and NK3 Ligands in the Design of New Multifunctional μ/δ-Opioid Agonist–Neurokinin Antagonist Peptidomimetics

Harnessing the Anti-Nociceptive Potential of NK2 and NK3 Ligands in the Design of New Multifunctional μ/δ-Opioid Agonist–Neurokinin Antagonist Peptidomimetics

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

Influence of G protein-biased agonists of μ-opioid receptor on addiction-related behaviors

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