Nicotinic acetylcholine receptors insects

But by far one of the best studied agonists of the nicotinic acetylcholine receptor is nicotine. It occurs in more than 64 species of plants around the world, including the well-known tobacco plant, which likely utilizes nicotine as a defense against insects that express nicotine receptors in their body and are therefore vulnerable to its toxicity. 

The modes of action of different alkaloids are diverse. For example, nicotine binds to and affects nicotinic acetylcholine receptors and shows toxicity. A recent molecular 3D model suggests that both acetylcholine and nicotine bind to the same pocket formed in a nicotinic acetylcholine receptor.15 Morphine binds to and activates opioid receptors, transmembrane-spanning G protein-coupled receptors, in the central nervous system of humans.16 Caffeine, which is structurally similar to adenine, inhibits cyclic AMP phosphodiesterase activity and inhibits the degradation of cAMP, thus exerting a toxic effect on insects 17 in human beings, binding of caffeine to the adenosine A2A receptor induces wakefulness.18 Atropine binds to muscarinic acetylcholine receptors, competing with acetylcholine, and blocks neurotransmission.1... 

The insect GABA receptor-chloride ionophore complex is found in the CNS and also at peripheral neuromuscular sites. GABA receptors belong to a superfamily of ligand-gated ion channels known as Cys-loop receptors that include nicotinic acetylcholine receptors and glutamate-gated chloride channels (Lester, 2004). Cys-loop receptors are so named because... 

The nicotinic acetylcholine receptors of the neural excitatory cholinergic system are the targets for both nicotine and neonicotinoids in mammals and insects. 

Nicotine and neonicotinoids are agonists, both of which act at the nicotinic acetylcholine receptor -Na" /K+ ionophore. The structural differences between the insect and mammalian receptors define the selectivity of neonicotinoid toxicity to insects and nicotine toxicity to vertebrates. The proposed concept of the neonicotinoid electronegative pharmacophore... 

Some toxic consequences of neonicotinoids for nontarget beneficial aquatic and terrestrial arthropods such as bees can be expected since these creatures have nicotinic acetylcholine receptors as functional components of the cholinergic system similar to those of insect pests. Surprisingly, neonicotinoid toxicity to numerous nontarget insect species and wildlife marker vertebrates, for example, rainbow trout, is lower than expected. In general, the environmental safety of neonicotinoids surpasses that of other insecticides. 

The toxicokinetics of the thianicotinyl thiamethoxam is similar to that of imidacloprid. When applied orally to rats, goats, or chickens, thiamethoxam is rapidly and almost quantitatively absorbed. Its excretion, predominantly in urine, is fast. Accumulation in tissues is negligible. Thiamethoxam itself does not bind strongly to the neonicotinoid binding site of the nicotinic acetylcholine receptor but it is reported to be converted to clothianidin, a neonicotinoid with high affinity for the insect receptors, in insects and plants (Figure 6). It is possible that this activation proceeds via formation of an N-desmethyl thiamethoxam intermediate, another... 

Little is known regarding chronic toxicity of nithiazine in humans or animals. It is reasonable to conclude, however, based on the data obtained in animal studies and in vitro tests, and on nithiazine affinity for insect nicotinic acetylcholine receptors, that nithiazine toxicity to humans and domestic animals or pets is low. 

Stemofoline is an insecticidal alkaloid produced in the leaves and stems of the plant Stemona japonica. It has a good spectrum of activity, with rapid action, and is a potent agonist of the nicotinic acetylcholine receptor in insects. These features make it a promising lead, except that its highly complex polycyclic structure is a real challenge for synthesis (Figure 3). 

R.J. Lind, D.T. Greenhow, J. Blythe, J. Goodchild, E. Hirst, S.J. Dunbar and F.G.P. Earley, Cyanotropanes Novel Chemistry Interacting at the Insect Nicotinic Acetylcholine Receptor in BCPC Conference - Pests Diseases, British Crop Protection Council, 2002, Vol. 1, pp. 145-152. 

A chloroform extract from the seeds of Delphinium plants was shown to be toxic to a number of insect species, and to have a very high affinity for the nicotinic acetylcholine receptor of the housefly. The major active fraction of the extract was an alkaloid, methyllycaconitine (MLA). A pure sample of MLA.citrate showed similar insecticidal activity to the crude extract, and had a similarly high affinity for the acetylcholine receptor. Previous experiments on a vertebrate preparation had indicated an action of MLA on the nicotinic acetylcholine receptor, but the concentrations used were many times greater than those affecting the housefly receptor. There may therefore be significant differences between the acetylcholine receptors of insects and vertebrates, and MLA could be a very useful tool for studying these differences. 

One target of interest in the search for new insecticides is the nicotinic acetylcholine receptor. Chemicals which act at this site are known to kill insects, and two are used as insecticides. These are nicotine, which has been used for over 200 years, mainly against aphids and thrips, and Padan, an insecticide used against rice pests, which was derived from a toxin produced by marine worms of the genus Nereis (1). The fact that one of these insecticides was derived from a plant and one from an animal underlines the... 

Besides an electron-withdrawing heterocyclic ring, they have a nitro-methylene, nitroimine, or cyanoimine group that can distinguish the insect receptor from the vertebrate nicotinic acetylcholine receptor (Tomizawa et al., 1995a, 1995b Yamamoto et al., 1995). 

Cartap is also an important insecticide acting at the nicotinic acetylcholine receptor site. It causes insects to stop feeding, is systemic, and has a low mammalian toxicity. It should therefore be a perfect insecticide. Cartap is not toxic per se, but is biologically converted to the cholinergic agonist nereistoxin, described later. 

Tomizawa, M., Otsuka, H., Miyamoto, T., Eldefrawi, M.E., and Yamamoto, I. 1995a. Pharmacological characteristics of insect nicotinic acetylcholine-receptor with its ion-channel and the comparison of the effect of nicotinoids and neonico-tinoids. /. Pest. Sci., 20, 57-64. 

Table I. Amino acid sequences in loop D of vertebrate and insect nicotinic acetylcholine receptors.

The cholinergic system in insects is the main target of insecticides. One class of molecules, the neonicotinoids, induces direct activation of the neuronal nicotinic acetylcholine receptors (nAChRs). In the honey bee these receptors are mainly distributed in the olfactory pathways that link sensory neurons to antennal lobes and mushroom bodies. These structures seem to play an important role in olfactory conditioning. We have previously shown that cholinergic antagonists injected in different parts of the brain impaired the formation and retrieval of olfactory memory. We then advanced the hypothesis that, through the activation of the nAChR, the neonicotinoid imidacloprid (IMI) would lead to facilitation of the memory trace. 

The synthesis of this compound was first described by Agro Kanesho [16]. Further preparations have been discussed in Section 29.2.3.4. As with all neonicoti-noids, AKD-1022 (12) interacts with nicotinic acetylcholine receptors however, it is much less potent than imidacloprid (8) and other commercial neonicotinoids. In particular, this has been demonstrated with Myzus and Drosophila membranes [23], as well as on American cockroaches [33]. It has been speculated that AKD-1022 (12), as a basic molecule, is ionized in the fluids of insects and, therefore, reaches the synapse only slowly through the lipophilic cuticles and the ion barriers. During retarded movement, the compound is prone to decompose, e.g., due to partial hydrolysis mediated enzymatically and/or non-enzymatically [33]. Therefore, acyclic nitroguanidines such as 19 may also contribute to the insecticidal activity observed in glasshouse and field studies. 

Although the structure of flonicamid (12) has some similarity to the neonicotinoids it does not bind to the nicotinic acetylcholine receptor as directly compared with nicotine and imidacloprid [37, 53]. However, flonicamid (12) is active on the A-type potassium channel currents. The current hypothesis is that flonicamid blockade of the A-type potassium channel in the presynaptic terminal underlies its lethal effect in insects. The loss of the A-type potassium rectifying current would lead to the disruption of controlled neurotransmitter release [53]. 

Biochemical experiments with several neonicotinoids on insect membranes showed that both, thiamethoxam and imidacloprid bind to the nicotinic acetylcholine receptor. Imidacloprid however inhibits the binding of thiamethoxam, while not competing for the same binding site. Thiamethoxam and other equally non-competitive neonicotinoids, which only served as research tools, share as a common structural element the N-methyl group at position 5 of the 1,3,5-oxadiazinane ring. 

In 1984, Mark E. Schroeder and Roger F. Flattum at Shell explored for nithiazine as the example, at which site these nitromethylene insecticides interact to effect their pharmacological activity. In cockroaches, the nicotinic acetylcholine receptor turned out to be the target. [140] In insects, the expression of these receptors is limited to the nervous system. There they reach a density, which is comparable only to the electric organ of the South American electric eel (Electro-phorus electricus). [ 141 ] From ligand displacement studies with nerve cell receptors of the American cockroach (Periplaneta americana), the honey-bee (Apis mellifera) and the common housefly (Musca domestica), the a-subrmit of the receptor became evident as the prime locus of interaction for neonicotinoids. 

Neonicotinoid insecticides act agonistically on insect nicotinic acetylcholine receptors (nAChRs). Like imidacloprid (IMI), all neonicotinoids bind with high affinity (Iso-values 1 nM) to binding sites on... 

Neonicotinoids target nicotinic acetylcholine receptors as is mostly known from studies with imidacloprid and conveniently sized lab model insects real target pests have not yet been used for technical reasons. Hence, conclusions, especially those on receptor sensitivity, should be taken with care. On the other hand, radioligand binding studies, which usually do not impose technical hurdles, have been widely performed with neonicotinoids using membranes from target and non-target insects. 

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