Search

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

The knowledge of the scorpion fauna of Iraq and its geographical distribution is limited. Our review reveals the presence in this country of 19 species belonging to 13 genera and five families: Buthidae, Euscorpiidae, Hemiscorpiidae, Iuridae and Scorpionidae. Buthidae is, with nine genera and 15 species, the richest and the most diverse family in Iraq. Synonymies of several scorpion species were reviewed. Due to erroneous identifications and locality data, we exclude 18 species of scorpion from the list of the Iraqi fauna. The geographical distribution of Iraqi scorpions is discussed. Compsobuthus iraqensisAl-Azawii, 2018, syn. nov. is synonymized with C. matthiesseni (Birula, 1905).

Knowledge regarding the smoking prevalence among the Kurdistan general population is not clear, at least for males. Here in the Kurdistan Youth Smoking Survey and Behaviours (KYSS&B) we tried to further expand our knowledge about the smoking profile of school students across Kurdistan. Five hundred students from four Zakho male basic schools were taken to participate in the study to determine the prevalence of smoking and socio-demographical factors associating with smoking among students aged 12 to 15 years. The KYSS&B questionnaire included various parameters such as age, gender, friends, parent history and blood groups. This study showed that the prevalence of students who ever tried smoking was 74%; about 65% of them started at age 12 years or less. Although the majority of participants (95%) knew that smoking is harmful and had negative impact on human health, 18% of them thought that they will never quit smoking. The study concluded that there was no strong association between family monthly income, parent education level and blood groups. On the other hand, the three most critical factors connected with smoking habit reported by students were age, peer influence and father smoking.

Insect toxins comprise a diverse array of chemicals ranging from small molecules, polyamines and peptide toxins. Many target nervous system and neuromuscular ion channels and so rapidly affect the behaviour of animals to which the toxin is applied or injected. Other modes of action have also been identified. Wasps, bees, flies, beetles and ants generate a rich arsenal of channel-active toxins, some of which offer selective pharmacological probes that target particular ion channels, while others act on more than one type of channel. Philanthotoxins from the digger wasp have been fruitful in adding to our understanding of ligand-gated ion channels both in the nervous system and at neuromuscular junctions. Fire ants produce the toxic alkaloid solenopsin, a molecule which has stimulated attempts to generate synthetic compounds with insecticidal activity. Apamin from bee venom targets calcium-activated potassium channels, which can in turn influence the release of neuropeptides. Melittin, another bee venom component, is a membrane-acting peptide. The saliva of the assassin bug contains toxins that target the voltage-gated calcium channels of their insect prey. Certain beetles produce diamphotoxin, a haemolytic peptide toxin with traditional use as an arrow poison and others generate leptinotarsin with similar properties. Mastoparan is a powerful peptide toxin present in the venom of wasps. Its toxic actions can be engineered out leaving a potent antimicrobial molecule of interest. In this short review we describe the actions of selected insect toxins and evaluate their potential as neuroactive pharmacological tools, candidate lead molecules for insect control and therapeutic candidates with potential antimicrobial, antiviral and anti-cancer applications.

Philanthotoxin-433 (PhTX-433) is an active component of the venom from the Egyptian digger wasp, Philanthus triangulum. PhTX-433 inhibits several excitatory ligand-gated ion channels, and to improve selectivity two synthetic analogues, PhTX-343 and PhTX-12, were developed. Previous work showed a 22-fold selectivity of PhTX-12 over PhTX-343 for embryonic muscle-type nicotinic acetylcholine receptors (nAChRs) in TE671 cells. We investigated their inhibition of different neuronal nAChR subunit combinations as well as of embryonic muscle receptors expressed in Xenopus oocytes. Whole-cell currents in response to application of acetylcholine alone or co-applied with PhTX analogue were studied by using two-electrode voltage-clamp. α3β4 nAChRs were most sensitive to PhTX-343 (IC50 = 12 nM at −80 mV) with α4β4, α4β2, α3β2, α7 and α1β1γδ being 5, 26, 114, 422 and 992 times less sensitive. In contrast α1β1γδ was most sensitive to PhTX-12 along with α3β4 (IC50 values of 100 nM) with α4β4, α4β2, α3β2 and α7 being 3, 3, 26 and 49 times less sensitive. PhTX-343 inhibition was strongly voltage-dependent for all subunit combinations except α7, whereas this was not the case for PhTX-12 for which weak voltage dependence was observed. We conclude that PhTX-343 mainly acts as an open-channel blocker of nAChRs with strong subtype selectivity.

Philanthotoxin-433 (PhTX-433) is the active component of the Egyptian solitary digger wasp, Philanthus triangulum, venom which non-selectively inhibits several excitatory ion channels. To improve selectivity two synthetic analogues, Philanthotoxin-343 (PhTX-343) and Philanthotoxin-12 (PhTX-12), were developed. Previous work showed a 22-fold selectivity for PhTX-12 on embryonic muscle-type nicotinic acetylcholine receptors (M-nAChR) naturally expressed in the TE671 cell line in comparison to PhTX-343. In this study, we investigated the pharmacological action of both analogues on different mammalian hetero-oligomeric neuronal nicotinic acetylcholine receptor (N-nAChR) subunit combinations expressed in Xenopus oocytes. Whole-cell currents in response to application of acetylcholine alone or co-applied with PhTX-analogue were studied electrophysiologically using two-electrode voltage-clamp at three different membrane holding potentials (VH = −60 mV, −80 mV and −100 mV). Concentration-inhibition curves were constructed and IC50 values estimated for each holding potential. The IC50 values for PhTX-343 inhibition of α3β4, α3β2, α4β2 and α4β4 peak currents at −100 mV were 0.077 µM (n=9), 3.20 µM (n=8), 0.170 µM (n=7) and 0.28 µM (n=6) respectively; for PhTX-12 they were 2.03 µM (n=8), 36.0 µM (n=10), 0.430 µM (n=7) and 1.82 µM (n=9) respectively; i.e. in contrast to M-nAChR, PhTX-343 was more potent than PhTX-12 in all cases. The potency of PhTX-343 was strongly augmented by holding the cell at more negative VH while this was not the case for PhTX-12 where weak voltage-dependence was observed. The variation in potency is most likely due to a single amino acid change in the β2/4 subunit pore lining region. Therefore, we conclude that PhTX-343 works as a potent open channel blocker of the mammalian heteromeric N-nAChR and has binding site deep in the channel while the PhTX-12 site is near to the outside of channel.