Insect Control: Biological and Synthetic Agents - Index of

R1
N N
O N H
indoxacarb. Thus, while providing important pielectron
interactions for local anesthetics, the aromatic
residue at Y20 in D4S6 might hinder access of
SCBIs to their binding site. In the German cockroach
sodium channel variant BgNav1-1A, alanine
substitution at positions F13 and Y20 of D4S6 had
somewhat different effects on the action of SCBIs
(Silver et al., 2009a). F13A substitution in the cockroach
channel did not change its sensitivity to
indoxacarb or DCJW, and made it hypersensitive
to metaflumizone. Furthermore, this mutation
greatly accelerated recovery of the channels from
block by metaflumizone. Therefore, in contrast to
its role in the rat Nav1.4 channel in the binding of
LAs and SCBIs, the phenyl functional group at position
F13 in D4S6 does not appear to participate in
the binding of SCBIs in BgNav1-1A channels, and
may in fact hinder the access of metaflumizone (but
not DCJW) to its binding site. As mentioned above,
alanine substitution of Y20 in D4S6 of rat Nav1.4
sodium channels increased sensitivity to DCJW 58fold
(Silver and Soderlund, 2007). The
corresponding mutation increased the sensitivity of
BgNa v1-1A channels 13-fold to DCJW and 11-fold
to metaflumizone. Thus, the aromatic side chain at
position 20 of D4S6, while crucial for local anesthetic
binding, does not appear to participate in
binding interactions with SCBIs, and in fact seems
to hinder access of SCBIs to their binding site in both
insect and mammalian sodium channels.
In conclusion, while F13 of D4S6 is important for
binding of both LAs and SCBIs in the rat Na v1.4
channel, it does not affect binding of DCJW in the
BgNav1-1A channel, and in fact hinders access of
metaflumizone to the binding site. Y20 in D4S6,
while crucial for LA binding, hinders access of
SCBIs to their site in both insect and mammalian
channels. The fact that residues involved in local
anesthetic binding sometimes antagonize binding
of SCBIs suggests that the SCBI and LA binding
R2
3-phenyl 1-phenylcarbamoyl-
2-pyrazolines
R1
N N
O N H
R3
R2
3,4-diphenyl 1-phenylcarbamoyl-
2-pyrazolines
Figure A1 Chemical evolution of the semicarbazone metaflumizone from pyrazolines.
sites overlap, but that the binding energy of SCBIs
comes in part from different residues, which have
yet to be identified.
References
CF 3
N NH
O N H
metaflumizone
A2: Addendum 59
CN
OCF 3
BASF Agricultural Products, 2007. Metaflumizone Worldwide
Technical Brochure.
Li, H.-L., Galue, A., Meadows, L., Ragsdale, D.S., 1999.
A molecular basis for the different local anesthetic affinities
of resting versus open and inactivated states of the
sodium channel. Mol. Pharmacol. 55, 134–141.
Rugg, D., Hair, J.A., 2007. Dose determination of a novel
formulation of metaflumizone plus amitraz for the
treatment and control of fleas (Ctenocephalides felis)
and ticks (Rhipicephalus sanguineus) on dogs. Vet.
Parasitol. 150, 203–208.
Salgado, V.L., Hayashi, J.H., 2007. Metaflumizone is a
novel sodium channel blocker insecticide. Vet. Parasitol.
150, 182–189.
Silver, K.S., Soderlund, D.M., 2005. State-dependent
block of rat Nav1.4 sodium channels expressed in
Xenopus oocytes by pyrazoline-type insecticides. Neurotoxicology
26, 397–406.
Silver, K.S., Soderlund, D.M., 2007. Point mutations at
the local anesthetic receptor site modulate the statedependent
block of rat Na v1.4 sodium channels by
pyrazoline-type insecticides. Neurotoxicology 28,
655–663.
Silver, K.S., Nomura, Y., Salgado, V.L., Dong, K., 2009a.
Role of the sixth transmembrane segment of domain IV
of the cockroach sodium channel in the action of sodium
channel blocker insecticides. Neurotoxicology 30,
613–621.
Silver, K.S., Song, W., Nomura, Y., Salgado, V.L., Dong,
K., 2009b. Mechanism of action of sodium channel
blocker insecticides (SCBIs) on insect sodium channels.
Pestic. Biochem. Physiol. in press, doi:10.1016/
j.pestbp.2009.09.001.
Song, W., Liu, Z., Dong, K., 2006. Molecular basis of
differential sensitivity of insect sodium channels to
DCJW, a bioactive metabolite of the oxadiazine insecticide
indoxacarb. Neutotoxicol 27, 237–244.