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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, Schistocerca gregaria .
- Source :
-
Molecules (Basel, Switzerland) [Molecules] 2021 Nov 19; Vol. 26 (22). Date of Electronic Publication: 2021 Nov 19. - Publication Year :
- 2021
-
Abstract
- 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 ( Schistocerca gregaria ) 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 <subscript>50</subscript> = 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 <subscript>50</subscript> (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 <subscript>50</subscript> = 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 <subscript>50</subscript> = 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.
- Subjects :
- Acetylcholine chemistry
Acetylcholine metabolism
Amino Acids chemistry
Amino Acids metabolism
Animals
Grasshoppers metabolism
Insect Proteins antagonists & inhibitors
Insect Proteins metabolism
Nicotinic Antagonists pharmacology
Phenols pharmacology
Polyamines pharmacology
Protein Conformation
Receptors, Nicotinic metabolism
Tyrosine chemistry
Tyrosine pharmacology
Grasshoppers chemistry
Insect Proteins chemistry
Nicotinic Antagonists chemistry
Phenols chemistry
Polyamines chemistry
Receptors, Nicotinic chemistry
Tyrosine analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1420-3049
- Volume :
- 26
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Molecules (Basel, Switzerland)
- Publication Type :
- Academic Journal
- Accession number :
- 34834099
- Full Text :
- https://doi.org/10.3390/molecules26227007