Philanthotoxin analogues that selectively inhibit ganglionic nicotinic acetylcholine receptors with exceptional potency

Kachel, Hamid S.; Franzyk, Henrik; Mellor, Ian R.

Abstract

Philanthotoxin-433 (PhTX-433) is an active component of the venom from the Egyptian digger wasp, Philanthus triangulum. PhTX-433 non-selectively inhibits several excitatory ligand-gated ion channels, and we recently showed that its synthetic analogue, PhTX-343, exhibits strong selectivity for neuronal over muscle-type nicotinic acetylcholine receptors (nAChRs). Here we examined the action of seventeen analogues of PhTX-343 against ganglionic (α3β4) and brain (α4β2) nAChRs expressed in Xenopus oocytes by using two-electrode voltage-clamp at -100 mV. IC50 values for PhTX-343 inhibition of α3β4 and α4β2 receptors were 7.7 nM and 80 nM, respectively. All of the studied analogues had significantly higher potency at α3β4 nAChRs with IC50 values as low as 0.16 nM and with up to a 91-fold selectivity for α3β4 over α4β2 receptors. We conclude that PhTX-343 analogues displaying both a saturated ring and an aromatic moiety in the hydrophobic headgroup of the molecule demonstrate exceptional potency and selectivity for α3β4 nAChRs. 2

Citation

Kachel, H. S., Franzyk, H., & Mellor, I. R. (2019). Philanthotoxin analogues that selectively inhibit ganglionic nicotinic acetylcholine receptors with exceptional potency. Journal of Medicinal Chemistry, 62(13), 6214-6222. https://doi.org/10.1021/acs.jmedchem.9b00519

• Journal Article Type: Article
• Acceptance Date: Jun 5, 2019
• Online Publication Date: Jun 24, 2019
• Publication Date: Jun 24, 2019
• Deposit Date: Jun 25, 2019
• Publicly Available Date: Jun 25, 2020
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 1520-4804
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 62
• Issue: 13
• Pages: 6214-6222
• DOI: https://doi.org/10.1021/acs.jmedchem.9b00519
• Keywords: nicotinic acetylcholine receptor; philanthotoxin; antagonism; open-channel block; Xenopus oocytes; two-electrode voltage clamp
• Public URL: https://nottingham-repository.worktribe.com/output/2228225
• Publisher URL: https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.9b00519
• Additional Information: This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Journal of Medicinal Chemistry, copyright ©American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org//10.1021/acs.jmedchem.9b00519
• Contract Date: Jun 25, 2019