Structure–activity relationship of the allosteric effects of ivermectin at human P2X4 and GABAA receptors

Meades, Jessica L., Bassetto, Marcella, Staiculescu, Marius C., Swaminath, Gayathri and Fountain, Samuel J. (2025) Structure–activity relationship of the allosteric effects of ivermectin at human P2X4 and GABAA receptors. British Journal of Pharmacology. ISSN 0007-1188

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Abstract

Background and purpose: Positive allosteric modulation of the P2X4 receptor is a potential route to providing cardiovascular benefit through enhancing flow-dependent arterial vasodilation and providing cardioprotection. However, ligands that selectively enhance P2X4 activity are absent. The broad-spectrum antiparasitic ivermectin (MK-933) is a known positive allosteric modulator of P2X4, but not selective for P2X4, acting to enhance the activity of other ion channels including the GABAA receptor through which its neurotoxic and anti-convulsant properties are mediated. Here, we combine complementary methodology to investigate the structure–activity relationship of ivermectin at human P2X4 and GABAA receptors. Experimental approach and key results: Intracellular Ca2+ and membrane potential assays in cell lines expressing human P2X4 or human GABAA α1β3γ2 receptor are used, respectively. A chemical library of ivermectin analogues are pharmacologically characterised at both receptors, and in silico techniques are used to identify ligand binding modes in human P2X4 to interpret pharmacological properties. We identify ivermectin-B1a as a positive allosteric modulation of P2X4, but full agonist at the GABAA α1β3γ2 receptor. We discover that the large disaccharide moiety of ivermectin-B1a is not required for activity. We identify an intersubunit transmembrane domain binding mode for ivermectin-B1a in P2X4 supported by the structure–activity relationship of ivermectin analogues. A series of novel compounds with selectivity for P2X4 over GABAA receptor are identified. Conclusions and implications: Ivermectin-B1a enhances P2X4 and GABAA α1β3γ2 receptor activity but through differing pharmacological mechanisms. We identify pharmacophore information for the development of positive allosteric modulators selective for human P2X4 over GABAA receptors.

Item Type:	Article
Additional Information:	DATA AVAILABILITY STATEMENT: The data that support the findings of this study are available from the corresponding author upon reasonable request, including the three-dimensional coordinates of our final model in complex with docked ivermectin-B1a. ACKNOWLEDGEMENTS: This work was funded by the British Heart Foundation (PG/16/69/32194) and a Biotechnology and Biological Sciences iCASE award with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Faculty \ School:	Faculty of Science > School of Biological Sciences
UEA Research Groups:	Faculty of Science > Research Groups > Cells and Tissues
Related URLs:	https://bpspubs.onlinelibrary.wiley.com/...
Depositing User:	LivePure Connector
Date Deposited:	30 Jun 2025 11:30
Last Modified:	30 Jun 2025 11:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/99776
DOI:	10.1111/bph.70121

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