The Effects of Structural Alterations in the Polyamine and Amino Acid Moieties of Philanthotoxins on Nicotinic Acetylcholine Receptor Inhibition in the Locust, <i>Schistocerca gregaria</i>

Alterations in the polyamine and amino acid (tyrosine) moieties of philanthotoxin-343 (PhTX-343) were investigated for their effects on the antagonism of nicotinic acetylcholine receptors (nAChRs) isolated from the locust (<i>Schistocerca gregaria</i>) mushroom body. Through whole-cell p...

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Autores principales:	Victoria L. Luck, David P. Richards, Ashif Y. Shaikh, Henrik Franzyk, Ian R. Mellor
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	philanthotoxin nicotinic acetylcholine receptor locust neuron patch-clamp Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/323019ba1285482aa81e01cc9063f5a9
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spelling	oai:doaj.org-article:323019ba1285482aa81e01cc9063f5a92021-11-25T18:29:08ZThe Effects of Structural Alterations in the Polyamine and Amino Acid Moieties of Philanthotoxins on Nicotinic Acetylcholine Receptor Inhibition in the Locust, <i>Schistocerca gregaria</i>10.3390/molecules262270071420-3049https://doaj.org/article/323019ba1285482aa81e01cc9063f5a92021-11-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/22/7007https://doaj.org/toc/1420-3049Alterations in the polyamine and amino acid (tyrosine) moieties of philanthotoxin-343 (PhTX-343) were investigated for their effects on the antagonism of nicotinic acetylcholine receptors (nAChRs) isolated from the locust (<i>Schistocerca gregaria</i>) mushroom body. Through whole-cell patch-clamp recordings, the philanthotoxin analogues in this study were shown to cause inhibition of the inward current when co-applied with acetylcholine (ACh). PhTX-343 (IC<sub>50</sub> = 0.80 μM at −75 mV) antagonised locust nAChRs in a use-dependent manner, suggesting that it acts as an open-channel blocker. The analogue in which both the secondary amine functionalities were replaced with methylene groups (i.e., PhTX-12) was ~6-fold more potent (IC<sub>50</sub> (half-maximal inhibitory concentration) = 0.13 μM at −75 mV) than PhTX-343. The analogue containing cyclohexylalanine as a substitute for the tyrosine moiety of PhTX-343 (i.e., Cha-PhTX-343) was also more potent (IC<sub>50</sub> = 0.44 μM at −75 mV). A combination of both alterations to PhTX-343 generated the most potent analogue, i.e., Cha-PhTX-12 (IC<sub>50</sub> = 1.71 nM at −75 mV). Modulation by PhTX-343 and Cha-PhTX-343 fell into two distinct groups, indicating the presence of two pharmacologically distinct nAChR groups in the locust mushroom body. In the first group, all concentrations of PhTX-343 and Cha-PhTX-343 inhibited responses to ACh. In the second group, application of PhTX-343 or Cha-PhTX-343 at concentrations ≤100 nM caused potentiation, while concentrations ≥ 1 μM inhibited responses to ACh. Cha-PhTX-12 may have potential to be developed into insecticidal compounds with a novel mode of action.Victoria L. LuckDavid P. RichardsAshif Y. ShaikhHenrik FranzykIan R. MellorMDPI AGarticlephilanthotoxinnicotinic acetylcholine receptorlocustneuronpatch-clampOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 7007, p 7007 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	philanthotoxin nicotinic acetylcholine receptor locust neuron patch-clamp Organic chemistry QD241-441
spellingShingle	philanthotoxin nicotinic acetylcholine receptor locust neuron patch-clamp Organic chemistry QD241-441 Victoria L. Luck David P. Richards Ashif Y. Shaikh Henrik Franzyk Ian R. Mellor The Effects of Structural Alterations in the Polyamine and Amino Acid Moieties of Philanthotoxins on Nicotinic Acetylcholine Receptor Inhibition in the Locust, <i>Schistocerca gregaria</i>
description	Alterations in the polyamine and amino acid (tyrosine) moieties of philanthotoxin-343 (PhTX-343) were investigated for their effects on the antagonism of nicotinic acetylcholine receptors (nAChRs) isolated from the locust (<i>Schistocerca gregaria</i>) mushroom body. Through whole-cell patch-clamp recordings, the philanthotoxin analogues in this study were shown to cause inhibition of the inward current when co-applied with acetylcholine (ACh). PhTX-343 (IC<sub>50</sub> = 0.80 μM at −75 mV) antagonised locust nAChRs in a use-dependent manner, suggesting that it acts as an open-channel blocker. The analogue in which both the secondary amine functionalities were replaced with methylene groups (i.e., PhTX-12) was ~6-fold more potent (IC<sub>50</sub> (half-maximal inhibitory concentration) = 0.13 μM at −75 mV) than PhTX-343. The analogue containing cyclohexylalanine as a substitute for the tyrosine moiety of PhTX-343 (i.e., Cha-PhTX-343) was also more potent (IC<sub>50</sub> = 0.44 μM at −75 mV). A combination of both alterations to PhTX-343 generated the most potent analogue, i.e., Cha-PhTX-12 (IC<sub>50</sub> = 1.71 nM at −75 mV). Modulation by PhTX-343 and Cha-PhTX-343 fell into two distinct groups, indicating the presence of two pharmacologically distinct nAChR groups in the locust mushroom body. In the first group, all concentrations of PhTX-343 and Cha-PhTX-343 inhibited responses to ACh. In the second group, application of PhTX-343 or Cha-PhTX-343 at concentrations ≤100 nM caused potentiation, while concentrations ≥ 1 μM inhibited responses to ACh. Cha-PhTX-12 may have potential to be developed into insecticidal compounds with a novel mode of action.
format	article
author	Victoria L. Luck David P. Richards Ashif Y. Shaikh Henrik Franzyk Ian R. Mellor
author_facet	Victoria L. Luck David P. Richards Ashif Y. Shaikh Henrik Franzyk Ian R. Mellor
author_sort	Victoria L. Luck
title	The Effects of Structural Alterations in the Polyamine and Amino Acid Moieties of Philanthotoxins on Nicotinic Acetylcholine Receptor Inhibition in the Locust, <i>Schistocerca gregaria</i>
title_short	The Effects of Structural Alterations in the Polyamine and Amino Acid Moieties of Philanthotoxins on Nicotinic Acetylcholine Receptor Inhibition in the Locust, <i>Schistocerca gregaria</i>
title_full	The Effects of Structural Alterations in the Polyamine and Amino Acid Moieties of Philanthotoxins on Nicotinic Acetylcholine Receptor Inhibition in the Locust, <i>Schistocerca gregaria</i>
title_fullStr	The Effects of Structural Alterations in the Polyamine and Amino Acid Moieties of Philanthotoxins on Nicotinic Acetylcholine Receptor Inhibition in the Locust, <i>Schistocerca gregaria</i>
title_full_unstemmed	The Effects of Structural Alterations in the Polyamine and Amino Acid Moieties of Philanthotoxins on Nicotinic Acetylcholine Receptor Inhibition in the Locust, <i>Schistocerca gregaria</i>
title_sort	effects of structural alterations in the polyamine and amino acid moieties of philanthotoxins on nicotinic acetylcholine receptor inhibition in the locust, <i>schistocerca gregaria</i>
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/323019ba1285482aa81e01cc9063f5a9
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The Effects of Structural Alterations in the Polyamine and Amino Acid Moieties of Philanthotoxins on Nicotinic Acetylcholine Receptor Inhibition in the Locust, <i>Schistocerca gregaria</i>

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