New Insecticide New Insecticide Modes of Action:Modes of Action:

Whence Selectivity?Whence Selectivity?

Joel CoatsJoel Coats

Professor of Entomology and ToxicologyProfessor of Entomology and Toxicology

Iowa State UniversityIowa State University

Ames, IowaAmes, Iowa

Outline Selectivity New Insecticide Classes

Neonictinoids Fipronil Chlorphenapyr Sulfluramid Spinosads Buprofezin Diafenthiauron Indoxacarb Metaflumazone Pymetrozine

Where have we been?Where have we been?

CHCl

CCl3

Cl

DDT

O

Cl

ClCl

Cl

Cl

Cl

dieldrin

Cl

Cl

ClCl

Cl

Cl

lindane

Where are we now, Where are we now, and where are we headed?and where are we headed?

NeonicotinoidsNeonicotinoids

NCl

N

NH

NNo2

Imidacloprid

Mode of Action

•Binds irreversibly to postsynaptic nicotinic acetlycholine receptors.

ImidaclopridImidacloprid

NeoNeo

ACHACH

NERVE SYNAPSENERVE SYNAPSE

nerve axonnerve axon

NeoNeo

Neonicotinoid: Acetylcholine AgonistNeonicotinoid: Acetylcholine AgonistNeonicotinoid: Acetylcholine AgonistNeonicotinoid: Acetylcholine Agonist

ACH

NeonicotinoidsNeonicotinoidsThiamethoxamThiamethoxam

Control wide range of Control wide range of sucking / chewing sucking / chewing pests like aphids, pests like aphids, thrips, termites, thrips, termites, weevils, beetles, weevils, beetles, wireworms, fire antswireworms, fire ants

Toxicity to non-targetsToxicity to non-targets Rat oral LDRat oral LD5050 a.i. = 1,563 mg/kg a.i. = 1,563 mg/kg

Rat dermal LDRat dermal LD5050 a.i. >2,000 mg/kg a.i. >2,000 mg/kg

Water solubility = 4,100 mg/LWater solubility = 4,100 mg/L

Neonicotinoids--ThiamethoxamNeonicotinoids--Thiamethoxam

FipronilFipronil

fipronil - Regentfipronil - Regent

Phenyl-pyrazole family

fipronil - primary fipronil - primary family member in family member in productionproduction

F3C Cl

ClN

N CN

SH2N

F3CO

Fipronil

Fipronil Mode of ActionFipronil Mode of Action

Acts as an inhibitor at the Acts as an inhibitor at the -aminobutyric -aminobutyric acid (GABA) receptor as a noncompetitive acid (GABA) receptor as a noncompetitive blocker of the GABA-gated chloride blocker of the GABA-gated chloride channel (similar to lindane and channel (similar to lindane and cyclodienes)cyclodienes)

Chemical and biological activation Chemical and biological activation producing equally toxic and sometime more producing equally toxic and sometime more persistent metabolites with same mode of persistent metabolites with same mode of actionaction

Cl- K+

Cl-

Cl-Cl-

GABA-gated Chloride Channel GABA-gated Chloride Channel

Nerve AxonNerve AxonNerve AxonNerve Axon

Na+

Cl-

Fipr

K+

Cl-

Cl-Cl-

Antagonist at GABA-gated Chloride Channel Antagonist at GABA-gated Chloride Channel

Fipronil Mode of ActionFipronil Mode of ActionFipronil Mode of ActionFipronil Mode of Action

Na+

Cl-

Selective Toxicity of FipronilSelective Toxicity of Fipronil

Vertebrate

Acute Mouse Oral LD50 = 41 mg/kg

Insect

Acute Housefly Contact LD50 = 0.13 mg/kg

ChlorfenapyrChlorfenapyr

Chlorfenapyr, AC-303,630

ChlorfenapyrChlorfenapyr

American Cyanamid American Cyanamid product, now BASFproduct, now BASF

Registered outside U.S. Registered outside U.S. for cottonfor cotton

Broad-spectrum Broad-spectrum insecticidal actioninsecticidal action

N

CH2

Br

F3C

CH3

ClO

C2H5

ChlorfenapyrChlorfenapyrOxidative PhosphorylationOxidative Phosphorylation

Chemiosmotic theory

Electron flow through the electron transport chain is accompanied by a transfer of protons

ATP synthesis driven by proton-motive force

Electron transport train uses O2 as final electron receptor

SulfluramidSulfluramid

CH3CH2 N S C C C C CCC

O

O

H

F

F F F F F F F

F F F F F F

CF3

sulfluramid

SpinosadsSpinosads

New class of potent natural New class of potent natural insecticidesinsecticides

O

N

R

R1

HO

O

O

OR5

H H

R6

R7

H H O OH

OR4

OR3

R2O

SPINOSADS

SpinosadsSpinosads

Mode of action – acts on the acetylcholine Mode of action – acts on the acetylcholine receptor to make it more excitable receptor to make it more excitable Overstimulation of the nerve results.Overstimulation of the nerve results.

Hypothesis currently considered most Hypothesis currently considered most plausible, although not really accepted as plausible, although not really accepted as the last wordthe last word

ACHACH

ACHACH

ACHACH

ACHACH

NERVE SYNAPSENERVE SYNAPSE

nerve axonnerve axon

Acetylcholine Receptor - SpinosadsAcetylcholine Receptor - SpinosadsAcetylcholine Receptor - SpinosadsAcetylcholine Receptor - Spinosads

Spyn

N

N

S

O

NC(CH3)3

CH(CH3)2

buprofezin

Buprofezin

Buprofezin – Mode of ActionBuprofezin – Mode of Action

Inhibits chitin synthesis/depositionInhibits chitin synthesis/deposition

Effect similar to benzoyl phenylureasEffect similar to benzoyl phenylureas

Insects die when newly moltedInsects die when newly molted

IGRIGR

DiafenthiuronDiafenthiuron

O

CH(CH3)2

CH(CH3)2

HN C

S

NHC(CH3)3

diafenthiuron

Diafenthiuron- Mode of ActionDiafenthiuron- Mode of Action

Inhibits ATPase in mitochondriaInhibits ATPase in mitochondria

Blocks utilization of energy (ATP)Blocks utilization of energy (ATP)

Thiourea compoundThiourea compound

IndoxacarbIndoxacarb

O

N

N

C

OOCH3

N OCH3

OO

OCF3

Cl

indoxacarb

Indoxacarb – Mode of ActionIndoxacarb – Mode of Action

Blocks sodium channel in nerve axonBlocks sodium channel in nerve axon

Inhibits propagation of nerve potentialInhibits propagation of nerve potential

Oxadiazine compoundOxadiazine compound

Indox

Na+Na+

K+

Cl-

Cl-Cl-

Nerve Potential PropagationNerve Potential Propagation

Indoxacarb effect on nerve axonIndoxacarb effect on nerve axonIndoxacarb effect on nerve axonIndoxacarb effect on nerve axon

Metaflumizone

MetaflumizoneMetaflumizone

Putative mode of action – blocks sodium Putative mode of action – blocks sodium channel in nerveschannel in nerves

Log P 4.7-5.4Log P 4.7-5.4

PymetrozinePymetrozine

HN

N

N

N

O

N

pymetrozine

Pymetrozine – Mode of ActionPymetrozine – Mode of Action

Inhibits feeding of sucking insectsInhibits feeding of sucking insects

Especially active on aphidsEspecially active on aphids

Pyridine azomethine compoundPyridine azomethine compound

ConclusionsConclusions

A number of very new classes of A number of very new classes of insecticides have been developed, with insecticides have been developed, with new modes of action.new modes of action.

Availability of products is changing, toward Availability of products is changing, toward newer classes of insecticides. newer classes of insecticides.

Selectivity is ever more important:Selectivity is ever more important:

to applicators, to livestock, pets, wildlife, to applicators, to livestock, pets, wildlife, environment, residues in food.environment, residues in food.

ConclusionsConclusions

Some of the new chemistry perpetuates Some of the new chemistry perpetuates non-selective insecticide toxicity.non-selective insecticide toxicity.

Some of it allows opportunities for safer, Some of it allows opportunities for safer, more selective insecticides.more selective insecticides.

QuestionsQuestions

How many and which modes of action How many and which modes of action should be screened for in non-target should be screened for in non-target bioassays? High throughput assays?bioassays? High throughput assays?

Can we predict which species will be most Can we predict which species will be most vulnerable and under what exposure vulnerable and under what exposure (conc., timing)?(conc., timing)?

The First McKim Conference: The First McKim Conference: Some Important QuestionsSome Important Questions

Best bioassays?Best bioassays?

Specificity and selectivity?Specificity and selectivity?

Extrapolation?Extrapolation?

Metabolic detoxification or activation?Metabolic detoxification or activation?

““If you’re not part of the solution…If you’re not part of the solution…you’re part of the precipitate.”you’re part of the precipitate.”

- Anon (C&EN)- Anon (C&EN)

Getting answers depends on Getting answers depends on the quality of “the hired help.”the quality of “the hired help.”

Steve Bradbury, circa 1984Steve Bradbury, circa 1984

PartPart of Jim McKim’s rich legacyof Jim McKim’s rich legacy