Philanthotoxin Analogues That Selectively Inhibit Ganglionic Nicotinic Acetylcholine Receptors with Exceptional Potency

Philanthotoxin-433 (PhTX-433) is an active component of the venom from the Egyptian digger wasp, Philanthus triangulum. PhTX-433 nonselectively 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 17 analogues of PhTX-343 against ganglionic (α3β4) and brain (α4β2) nAChRs expressed in Xenopus oocytes by using a two-electrode voltage clamp at −100 mV. IC₅₀ values for PhTX-343 inhibition of α3β4 and α4β2 receptors were 7.7 and 80 nM, respectively. All the studied analogues had significantly higher potency at α3β4 nAChRs with IC₅₀ values as low as 0.16 nM and with up to 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.