Synthetic route towards potential bivalent ligands possessing opioid and D2/D3 pharmacophores

Jevtić, Ivana; Penjisevic, Z Jelena; Ivanović, Darko; Kostić‐Rajačić, Sladjana

doi:10.2298/jsc181002105j

Cited by 4 publications

(7 citation statements)

References 23 publications

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“…Researchers of various groups reported novel analogues, including those of norsufentanil [ 10 ], carfentanil amides [ 11 ] or acrylic derivatives [ 12 ]. Fentanyl scaffold has also been used in the design of bivalent (multitarget) compounds to create mixed μ-/δ-OR ligands [ 13 , 14 , 15 ], or molecules joining even more distant pharmacophores like opioid receptor agonist and FAAH/MAGL hydrolases inhibitors [ 16 ], or opioid and dopamine receptors D2/D3 ligands [ 17 ]. Most excitingly, fentanyl has its place also in the most up-to-date trends of pain pharmacology that is in the research on biased μOR agonists which holds promise for finding strong analgesics without adverse effects.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…The initial research of the D 2 DAR/ΜOR heterobivalent ligands involved the synthesis of only three compounds of general formula 1, as proof of the synthetic concept. 14 Herein, the optimized synthesis of 13 novel compounds of the general formula 1, having 3 to 7 methylene groups in the linker, were synthesized according to the published procedure, 14 (Scheme 1). 2-Methoxyphenylpiperazine was chosen here rather than 3-methoxyphenylpiperazine 16 , since it is a more abundant structural unit in D2-like-DAR pharmacophores.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, a series of potential heterobivalent opioid-dopamine receptor ligands were designed and synthesized as a part of ongoing synthetic and pharmacological research in functionalized heterocycles. 14 The compounds included the both pharmacophores, joined by methylene linkers of various lengths (general structure 1, Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

μ-opioid/D2 dopamine receptor pharmacophore containing ligands: Synthesis and pharmacological evaluation

Jevtić

Penjisevic

Savic-Vujovic

et al. 2020

JSCS

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Herein, the synthesis and pharmacological evaluation of 13 novel compounds, designed as potential heterobivalent ligands for μ-opioid receptor (MOR) and dopamine D 2 receptors (D 2 DAR), are reported. The compounds consisted of anilido piperidine and N-aryl piperazine moieties, joined by a variable-length methylene linker. The two moieties represent MOR and D 2 DAR pharmacophores, respectively. The synthesis encompassed four steps, securing the final products in 28-42 % overall yields. The approach has a considerable synthetic potential, providing access to various related structures. Pharmacological tests involved in vitro competitive assay for D 2 DAR using [ 3 H] spiperon, as a standard radioligand, and in vivo antinociceptive tests for MOR. The measured dopamine affinities were modest to low, while antinociceptive activity was completely absent. Therefore, the compounds of the general structure prepared in this research are unlikely to be useful as opioid-dopamine receptor heterobivalent ligands.

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“…The possibility to employ a substructure of fentanyl (4-anilidopiperidine) in MOR/D 2 R multitarget ligands was investigated by Jevtić et al [ 76 , 77 ]. The D 2 R pharmacophoric element to be incorporated was N -arylpiperazine which is present in D 2 R ligands such as aripiprazole ( 5.1 , Figure 6 ) or pribedil ( 5.2 ).…”

Section: Fentanyl-based Mtas Targeting Mor and D 2 ...mentioning

confidence: 99%

Fentanyl Structure as a Scaffold for Opioid/Non-Opioid Multitarget Analgesics

Lipiński

Matalińska

2022

IJMS

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One of the strategies in the search for safe and effective analgesic drugs is the design of multitarget analgesics. Such compounds are intended to have high affinity and activity at more than one molecular target involved in pain modulation. In the present contribution we summarize the attempts in which fentanyl or its substructures were used as a μ-opioid receptor pharmacophoric fragment and a scaffold to which fragments related to non-opioid receptors were attached. The non-opioid ‘second’ targets included proteins as diverse as imidazoline I2 binding sites, CB1 cannabinoid receptor, NK1 tachykinin receptor, D2 dopamine receptor, cyclooxygenases, fatty acid amide hydrolase and monoacylglycerol lipase and σ1 receptor. Reviewing the individual attempts, we outline the chemistry, the obtained pharmacological properties and structure-activity relationships. Finally, we discuss the possible directions for future work.

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Synthetic route towards potential bivalent ligands possessing opioid and D2/D3 pharmacophores

Cited by 4 publications

References 23 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

μ-opioid/D2 dopamine receptor pharmacophore containing ligands: Synthesis and pharmacological evaluation

Fentanyl Structure as a Scaffold for Opioid/Non-Opioid Multitarget Analgesics

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