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23 pages, 5612 KiB

Open AccessArticle

Analogs of 6-Bromohypaphorine with Increased Agonist Potency for α7 Nicotinic Receptor as Anti-Inflammatory Analgesic Agents

by Igor A. Ivanov, Andrei E. Siniavin, Victor A. Palikov, Dmitry A. Senko, Irina V. Shelukhina, Lyubov A. Epifanova, Lucy O. Ojomoko, Svetlana Y. Belukhina, Nikita A. Prokopev, Mariia A. Landau, Yulia A. Palikova, Vitaly A. Kazakov, Natalia A. Borozdina, Arina V. Bervinova, Igor A. Dyachenko, Igor E. Kasheverov, Victor I. Tsetlin and Denis S. Kudryavtsev

Mar. Drugs 2023, 21(6), 368; https://doi.org/10.3390/md21060368 - 20 Jun 2023

Cited by 1 | Viewed by 2521

Abstract

Hypaphorines, tryptophan derivatives, have anti-inflammatory activity, but their mechanism of action was largely unknown. Marine alkaloid L-6-bromohypaphorine with EC₅₀ of 80 μM acts as an agonist of α7 nicotinic acetylcholine receptor (nAChR) involved in anti-inflammatory regulation. We designed the 6-substituted hypaphorine analogs with increased potency using virtual screening of their binding to the α7 nAChR molecular model. Fourteen designed analogs were synthesized and tested in vitro by calcium fluorescence assay on the α7 nAChR expressed in neuro 2a cells, methoxy ester of D-6-iodohypaphorine (6ID) showing the highest potency (EC₅₀ 610 nM), being almost inactive toward α9α10 nAChR. The macrophages cytometry revealed an anti-inflammatory activity, decreasing the expression of TLR4 and increasing CD86, similarly to the action of PNU282987, a selective α7 nAChR agonist. 6ID administration in doses 0.1 and 0.5 mg/kg decreased carrageenan-induced allodynia and hyperalgesia in rodents, in accord with its anti-inflammatory action. Methoxy ester of D-6-nitrohypaphorine demonstrated anti-oedemic and analgesic effects in arthritis rat model at i.p. doses 0.05–0.26 mg/kg. Tested compounds showed excellent tolerability with no acute in vivo toxicity in dosages up to 100 mg/kg i.p. Thus, combining molecular modelling and natural product-inspired drug design improved the desired activity of the chosen nAChR ligand. Full article

(This article belongs to the Special Issue Honoring Prof. Dr. Valentin A. Stonik for His Outstanding Contribution to Marine Natural Product Chemistry on the Occasion of His 80th Birthday)

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17 pages, 2127 KiB

Open AccessArticle

6-Bromoindole Derivatives from the Icelandic Marine Sponge Geodia barretti: Isolation and Anti-Inflammatory Activity

by Xiaxia Di, Caroline Rouger, Ingibjorg Hardardottir, Jona Freysdottir, Tadeusz F. Molinski, Deniz Tasdemir and Sesselja Omarsdottir

Mar. Drugs 2018, 16(11), 437; https://doi.org/10.3390/md16110437 - 8 Nov 2018

Cited by 32 | Viewed by 6774

Abstract

An UPLC-qTOF-MS-based dereplication study led to the targeted isolation of seven bromoindole alkaloids from the sub-Arctic sponge Geodia barretti. This includes three new metabolites, namely geobarrettin A–C (1–3) and four known compounds, barettin (4), 8,9-dihydrobarettin (5), 6-bromoconicamin (6), and l-6-bromohypaphorine (7). The chemical structures of compounds 1–7 were elucidated by extensive analysis of the NMR and HRESIMS data. The absolute stereochemistry of geobarrettin A (1) was assigned by ECD analysis and Marfey’s method employing the new reagent l-N^α-(1-fluoro-2,4-dinitrophenyl)tryptophanamide (l-FDTA). The isolated compounds were screened for anti-inflammatory activity using human dendritic cells (DCs). Both 2 and 3 reduced DC secretion of IL-12p40, but 3 concomitantly increased IL-10 production. Maturing DCs treated with 2 or 3 before co-culturing with allogeneic CD4⁺ T cells decreased T cell secretion of IFN-γ, indicating a reduction in Th1 differentiation. Although barettin (4) reduced DC secretion of IL-12p40 and IL-10 (IC₅₀ values 11.8 and 21.0 μM for IL-10 and IL-12p40, respectively), maturing DCs in the presence of 4 did not affect the ability of T cells to secrete IFN-γ or IL-17, but reduced their secretion of IL-10. These results indicate that 2 and 3 may be useful for the treatment of inflammation, mainly of the Th1 type. Full article

(This article belongs to the Special Issue Marine Anti-inflammatory Agents)

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19 pages, 811 KiB

Open AccessFeature PaperReview

Natural Compounds Interacting with Nicotinic Acetylcholine Receptors: From Low-Molecular Weight Ones to Peptides and Proteins

by Denis Kudryavtsev, Irina Shelukhina, Catherine Vulfius, Tatyana Makarieva, Valentin Stonik, Maxim Zhmak, Igor Ivanov, Igor Kasheverov, Yuri Utkin and Victor Tsetlin

Toxins 2015, 7(5), 1683-1701; https://doi.org/10.3390/toxins7051683 - 14 May 2015

Cited by 29 | Viewed by 10458

Abstract

Nicotinic acetylcholine receptors (nAChRs) fulfill a variety of functions making identification and analysis of nAChR subtypes a challenging task. Traditional instruments for nAChR research are d-tubocurarine, snake venom protein α-bungarotoxin (α-Bgt), and α-conotoxins, neurotoxic peptides from Conus snails. Various new compounds of different structural classes also interacting with nAChRs have been recently identified. Among the low-molecular weight compounds are alkaloids pibocin, varacin and makaluvamines C and G. 6-Bromohypaphorine from the mollusk Hermissenda crassicornis does not bind to Torpedo nAChR but behaves as an agonist on human α7 nAChR. To get more selective α-conotoxins, computer modeling of their complexes with acetylcholine-binding proteins and distinct nAChRs was used. Several novel three-finger neurotoxins targeting nAChRs were described and α-Bgt inhibition of GABA-A receptors was discovered. Information on the mechanisms of nAChR interactions with the three-finger proteins of the Ly6 family was found. Snake venom phospholipases A₂ were recently found to inhibit different nAChR subtypes. Blocking of nAChRs in Lymnaea stagnalis neurons was shown for venom C-type lectin-like proteins, appearing to be the largest molecules capable to interact with the receptor. A huge nAChR molecule sensible to conformational rearrangements accommodates diverse binding sites recognizable by structurally very different compounds. Full article

(This article belongs to the Special Issue Selected Papers from the 5th Venoms to Drugs Meeting)

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12 pages, 531 KiB

Open AccessArticle

6-Bromohypaphorine from Marine Nudibranch Mollusk Hermissenda crassicornis is an Agonist of Human α7 Nicotinic Acetylcholine Receptor

by Igor E. Kasheverov, Irina V. Shelukhina, Denis S. Kudryavtsev, Tatyana N. Makarieva, Ekaterina N. Spirova, Alla G. Guzii, Valentin A. Stonik and Victor I. Tsetlin

Mar. Drugs 2015, 13(3), 1255-1266; https://doi.org/10.3390/md13031255 - 12 Mar 2015

Cited by 25 | Viewed by 8374

Abstract

6-Bromohypaphorine (6-BHP) has been isolated from the marine sponges Pachymatisma johnstoni, Aplysina sp., and the tunicate Aplidium conicum, but data on its biological activity were not available. For the nudibranch mollusk Hermissenda crassicornis no endogenous compounds were known, and here we describe the isolation of 6-BHP from this mollusk and its effects on different nicotinic acetylcholine receptors (nAChR). Two-electrode voltage-clamp experiments on the chimeric α7 nAChR (built of chicken α7 ligand-binding and glycine receptor transmembrane domains) or on rat α4β2 nAChR expressed in Xenopus oocytes revealed no action of 6-BHP. However, in radioligand analysis, 6-BHP competed with radioiodinated α-bungarotoxin for binding to human α7 nAChR expressed in GH₄C₁ cells (IC₅₀ 23 ± 1 μM), but showed no competition on muscle-type nAChR from Torpedo californica. In Ca²⁺-imaging experiments on the human α7 nAChR expressed in the Neuro2a cells, 6-BHP in the presence of PNU120596 behaved as an agonist (EC₅₀ ~80 μM). To the best of our knowledge, 6-BHP is the first low-molecular weight compound from marine source which is an agonist of the nAChR subtype. This may have physiological importance because H. crassicornis, with its simple and tractable nervous system, is a convenient model system for studying the learning and memory processes. Full article

(This article belongs to the Special Issue Emerging Marine Toxins)

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