1. Philanthotoxin Analogues That Selectively Inhibit Ganglionic Nicotinic Acetylcholine Receptors with Exceptional Potency
- Author
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Ian R. Mellor, Hamid S. Kachel, and Henrik Franzyk
- Subjects
philanthotoxin ,Voltage clamp ,Xenopus ,Nicotinic Antagonists ,open-channel block ,Receptors, Nicotinic ,01 natural sciences ,Xenopus laevis ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Discovery ,Polyamines ,Animals ,two-electrode voltage clamp ,nicotinic acetylcholine receptor ,Receptor ,Ion channel ,Xenopus oocytes ,030304 developmental biology ,Acetylcholine receptor ,0303 health sciences ,biology ,Philanthotoxin ,biology.organism_classification ,antagonism ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Nicotinic agonist ,chemistry ,Drug Design ,Oocytes ,Biophysics ,Excitatory postsynaptic potential ,Molecular Medicine ,Female - 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 (?3?4) and brain (?4?2) nAChRs expressed in Xenopus oocytes by using two-electrode voltage-clamp at -100 mV. IC50 values for PhTX-343 inhibition of ?3?4 and ?4?2 receptors were 7.7 nM and 80 nM, respectively. All of the studied analogues had significantly higher potency at ?3?4 nAChRs with IC50 values as low as 0.16 nM and with up to a 91-fold selectivity for ?3?4 over ?4?2 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 ?3?4 nAChRs. 2
- Published
- 2019
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