The synthesis and pharmacological evaluation of (±)-2, 3- seco-fentanyl analogues

Ivanović, Darko; Mićović, Ivan V.; Vuckovic, Milica; Prostran, S Milica; Todorović, Zoran; Ivanovic, R Evica; Kiricojevic, D Vesna; Djordjević, Jelena; Dosen-Micovic, I Ljiljana

doi:10.2298/jsc0411955i

Cited by 7 publications

(5 citation statements)

References 26 publications

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“…To the best of our knowledge, the synthesis of F02 was reported before [ 41 ], however no data as to its analgesic activity or opioid receptor affinity were disclosed. The here presented binding data are in line with pharmacological characteristics of another acyclic derivative 2,3-seco-fentanyl for which it was found that it is about 40 times weaker an analgesic than fentanyl [ 42 ].…”

Section: Resultssupporting

confidence: 82%

Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis

et al. 2019

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Interactions of 21 fentanyl derivatives with μ-opioid receptor (μOR) were studied using experimental and theoretical methods. Their binding to μOR was assessed with radioligand competitive binding assay. A uniform set of binding affinity data contains values for two novel and one previously uncharacterized derivative. The data confirms trends known so far and thanks to their uniformity, they facilitate further comparisons. In order to provide structural hypotheses explaining the experimental affinities, the complexes of the studied derivatives with μOR were modeled and subject to molecular dynamics simulations. Five common General Features (GFs) of fentanyls’ binding modes stemmed from these simulations. They include: GF1) the ionic interaction between D147 and the ligands’ piperidine NH+ moiety; GF2) the N-chain orientation towards the μOR interior; GF3) the other pole of ligands is directed towards the receptor outlet; GF4) the aromatic anilide ring penetrates the subpocket formed by TM3, TM4, ECL1 and ECL2; GF5) the 4-axial substituent (if present) is directed towards W318. Except for the ionic interaction with D147, the majority of fentanyl-μOR contacts is hydrophobic. Interestingly, it was possible to find nonlinear relationships between the binding affinity and the volume of the N-chain and/or anilide’s aromatic ring. This kind of relationships is consistent with the apolar character of interactions involved in ligand–receptor binding. The affinity reaches the optimum for medium size while it decreases for both large and small substituents. Additionally, a linear correlation between the volumes and the average dihedral angles of W293 and W133 was revealed by the molecular dynamics study. This seems particularly important, as the W293 residue is involved in the activation processes. Further, the Y326 (OH) and D147 (Cγ) distance found in the simulations also depends on the ligands’ size. In contrast, neither RMSF measures nor D114/Y336 hydrations show significant structure-based correlations. They also do not differentiate studied fentanyl derivatives. Eventually, none of 14 popular scoring functions yielded a significant correlation between the predicted and observed affinity data (R < 0.30, n = 28).

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Section: Resultssupporting

confidence: 82%

Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis

et al. 2019

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“…One of them, diampromide ( 1S ) which produces effects similar to other opioid analgesics, and is around the same potency as morphine with an ED 50 of 4 mg/kg [71,72], another is 2,3-seco-fentanyl ( 2S ) whose central-analgesic activity was found to be 40-times lower than fentanyl, but still 5–6-times higher than that of morphine (Supplementary Information 2)[73]. …”

Section: Synthesis and Biological Activity Of Compounds In The Fentanylmentioning

confidence: 99%

Fentanyl-Related Compounds and Derivatives: Current Status and Future Prospects for Pharmaceutical Applications

2014

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Fentanyl and its analogs have been mainstays for the treatment of severe to moderate pain for many years. In this review, we outline the structural and corresponding synthetic strategies that have been used to understand the structure–biological activity relationship in fentanyl-related compounds and derivatives and their biological activity profiles. We discuss how changes in the scaffold structure can change biological and pharmacological activities. Finally, recent efforts to design and synthesize novel multivalent ligands that act as mu and delta opioid receptors and NK-1 receptors are discussed.

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“…120 times more potent than the (-)-enantiomer and 16-19 times more potent than both the (±)-trans-diastereomer and fentanyl. 7 Voluminous 3-alkyl groups reduce the activity, 5,8 and a 3-carbomethoxy function confers potency similar to that of fentanyl 9a,10 while 3-hydroxy, 11,12 3-methoxy, 13 and 3-fluorine 14 substituents were not evaluated pharmacologically.…”

mentioning

confidence: 99%

Synthesis of Orthogonally Protected (±)-3-Amino-4-anilidopiperidines and (±)-3-N-Carbomethoxyfentanyl

et al. 2017

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The synthesis of orthogonally protected cis- and trans-3-amino-4-anilidopiperidine derivatives has been accomplished in six steps, starting from readily accessible 4-piperidone derivatives. The last three steps, i.e., N-acylation, Hofmann rearrangement, and carbamate cleavage, involved separated (±)-cis and (±)-trans intermediates. Complete retention of configuration was observed at position 3 of the piperidine ring. Specifically protected positions 1 and 3 at the piperidine scaffold allow for selective deprotection and introduction of diverse substituents at the respective nitrogen sites. The orthogonally protected anilidopiperidines open avenues to potentially pharmacologically active compounds, including opioids and various bivalent ligands for G protein-coupled receptors. In addition, a prototype of a novel class of fentanyl derivatives, possessing a 3-amino group, was synthesized by using the same approach.

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The synthesis and pharmacological evaluation of (±)-2, 3- seco-fentanyl analogues

Cited by 7 publications

References 26 publications

Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis

Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis

Fentanyl-Related Compounds and Derivatives: Current Status and Future Prospects for Pharmaceutical Applications

Synthesis of Orthogonally Protected (±)-3-Amino-4-anilidopiperidines and (±)-3-N-Carbomethoxyfentanyl

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