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.

Philanthotoxin-433（PhTX-433）是埃及挖掘蜂Philanthus triangulum毒液中的活性成分。PhTX-433对多种兴奋性配体门控离子通道具有非选择性抑制作用，我们近期研究表明，其合成类似物PhTX-343对神经元型而非肌型烟碱乙酰胆碱受体（nAChRs）表现出强烈的选择性。在本研究中，我们通过在-100 mV下使用双电极电压钳技术，考察了17种PhTX-343类似物对表达于非洲爪蟾卵母细胞中的节后（α3β4）和脑（α4β2）型nAChRs的作用。PhTX-343抑制α3β4和α4β2受体的半数抑制浓度（IC50）值分别为7.7和80 nM。所有研究中的类似物在α3β4 nAChRs上均表现出显著更高的效力，其IC50值低至0.16 nM，对α3β4受体的选择性高达91倍。我们得出结论，在分子的疏水头基团中同时具有饱和环和芳香基团的PhTX-343类似物，表现出对α3β4 nAChRs的卓越效力和选择性。