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Mar. Drugs 2014, 12(4), 1859-1875; doi:10.3390/md12041859

Marine Natural Products Acting on the Acetylcholine-Binding Protein and Nicotinic Receptors: From Computer Modeling to Binding Studies and Electrophysiology

1
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street, 16/10, Moscow 117997, Russia
2
Elyakov Pacific Institute of Bioorganic Chemistry (PIBOC), Russian Academy of Sciences, Prospect 100 let Vladivostoku, 159, Vladivostok 690022, Russia
3
Department of Biochemistry I, Ruhr University, Bochum 44780, Germany
*
Author to whom correspondence should be addressed.
Received: 20 December 2013 / Revised: 20 February 2014 / Accepted: 11 March 2014 / Published: 28 March 2014
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Abstract

For a small library of natural products from marine sponges and ascidians, in silico docking to the Lymnaea stagnalis acetylcholine-binding protein (AChBP), a model for the ligand-binding domains of nicotinic acetylcholine receptors (nAChRs), was carried out and the possibility of complex formation was revealed. It was further experimentally confirmed via competition with radioiodinated α-bungarotoxin ([125I]-αBgt) for binding to AChBP of the majority of analyzed compounds. Alkaloids pibocin, varacin and makaluvamines С and G had relatively high affinities (Ki 0.5–1.3 μM). With the muscle-type nAChR from Torpedo californica ray and human neuronal α7 nAChR, heterologously expressed in the GH4C1 cell line, no competition with [125I]-αBgt was detected in four compounds, while the rest showed an inhibition. Makaluvamines (Ki ~ 1.5 μM) were the most active compounds, but only makaluvamine G and crambescidine 359 revealed a weak selectivity towards muscle-type nAChR. Rhizochalin, aglycone of rhizochalin, pibocin, makaluvamine G, monanchocidin, crambescidine 359 and aaptamine showed inhibitory activities in electrophysiology experiments on the mouse muscle and human α7 nAChRs, expressed in Xenopus laevis oocytes. Thus, our results confirm the utility of the modeling studies on AChBPs in a search for natural compounds with cholinergic activity and demonstrate the presence of the latter in the analyzed marine biological sources.
Keywords: marine natural compounds; acetylcholine-binding protein; nicotinic acetylcholine receptors; computer modeling; radioligand assay; electrophysiology marine natural compounds; acetylcholine-binding protein; nicotinic acetylcholine receptors; computer modeling; radioligand assay; electrophysiology
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MDPI and ACS Style

Kudryavtsev, D.; Makarieva, T.; Utkina, N.; Santalova, E.; Kryukova, E.; Methfessel, C.; Tsetlin, V.; Stonik, V.; Kasheverov, I. Marine Natural Products Acting on the Acetylcholine-Binding Protein and Nicotinic Receptors: From Computer Modeling to Binding Studies and Electrophysiology. Mar. Drugs 2014, 12, 1859-1875.

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