Nicotinoids

These nicotinoids are appreciably volatile (nicotine vapor pressure, 5.7 Pa at 25°C) and, although colorless Hquids when pure, rapidly darken upon exposure to air. They are highly basic = 1 x 10 , = 1 x 10 ) and readily form salts with acids and many metals. Nicotine sulfate [65-30-5],... 

Imidocloprid [105827-78-9] l-[(6-chloro-3-pytidinyl)methyl]-N-nitro-2-imida2ohdininiine (4) (bp 137—144°C, vp 0.2 )J.Pa at 20°C) is soluble to 0.51 g/L. It is a synthetic nicotinoid with both contact and systematic activity against aphids, leafhoppers, whiteflies, and other sucking insects. The rat LD qS are 424 male, 475 female (oral), and 5000 (dermal) mg/kg. 

Mode of Motion. Nicotine, anabasine, and imidocloprid affect the ganglia of the insect central nervous system, faciUtating transsynaptic conduction at low concentrations and blocking conduction at higher levels. The extent of ionisation of the nicotinoids plays an important role in both their penetration through the ionic barrier of the nerve sheath to the site of action and in their interaction with the site of action, which is befleved to be the acetylcholine receptor protein. There is a marked similarity in dimensions between acetylcholine and the nicotinium ion. 

Thus nicotinoids that have the highest insecticidal action have the highest piC and, consequently, exist largely in the ionized form at physiological pH. This produces the anomaly that the compounds that are most highly ionized react most rapidly with the receptor protein, yet they are less able to penetrate through the ionic barrier surrounding the insect nerve synapse. 

Many pesticides are not as novel as they may seem. Some, such as the pyre-throid and neonicotinoid insecticides, are modeled on natural insecticides. Synthetic pyrethroids are related to the natural pyrethrins (see Chapter 12), whereas the neo-nicotinoids share structural features with nicotine. In both cases, the synthetic compounds have the same mode of action as the natural products they resemble. Also, the synthetic pyrethroids are subject to similar mechanisms of metabolic detoxication as natural pyrethrins (Chapter 12). More widely, many detoxication mechanisms are relatively nonspecific, operating against a wide range of compounds that... 

At a more subtle level, behavioral disturbances may make it more difficult for animals to find food. Pyrethroids, carbamates, OPs, and neonicotinoids can disturb the foraging activity of bees (Thompson 2003). Interestingly, effects have been shown upon the wagtail dance of bees, and this disrupts communication between individuals as to the location of nectar-bearing plants. Also, the neonicotinoid imidacloprid has been shown to adversely affect conditioned responses such as proboscis extension of honeybees (Guez et al. 2001). Nicotinoids can disturb the functioning of cholinergic synapses, which are involved in the operation of the proboscis reflex as... 

Chavdarian, C.G., Sanders, E.B., Bassfield, R.L. (1982) Synthesis of Optically Active Nicotinoids. Journal of Organic Chemistry, 47, 1069-1073. 

Nicotinoids. Nicotine from tobacco was one of the earliest insecticides and was recommended for use in 1763 as a tea for the destruction of aphids (1,20). Nicotine [54-11 -3], L-l-methyl-2-(3 -pyridyl)pyrrolidine (1) (bp 247°C, d 1.009), is found in the leaves of Nicotiana tobacum and N. rustica (Solanaceae) in amounts ranging from 2 to 14%, and also is found in Duboisia hopwoodii and in Aesclepias syriaca. It occurs as the principal alkaloid along with small amounts of 12 other alkaloids of which nomicotine [494-97-3], 2-(3,-pyridyl)pyrrolidine (2) (bp 270°C, d 1.07 g/mL), and anabasine [494-52-0], l-2-(3 -pyridyl)piperidiae (3) (bp 281°C, d 1.048), are of insecticidal importance (see Alkaloids). Nomicotine occurs as both the D and L forms, the former in D. hopn oodii and the latter commonly predominating in Nicotiana. Anabasine is the chief alkaloid of Anabasis aphylla, where it occurs from 1—2% in the shoots and is found to ca 1% in Nicotianaglauca. 

Kanne, D.B., and Abood, L.G. 1988. Synthesis and biological characterization of pyridohomotropanes. structure-activity relationships of conformationally restricted nicotinoids. JMed Chem 31, 506-509. 

Tomizawa M and Casida JE (1999) Minor structural changes in nicotinoid insecticides confer differential sub-type selectivity for mammalian nicotinic acetylcholine receptors. British Journal of Pharmacology 127 115-122. 

Yamamoto I and Casida JE (1999) Nicotinoid Insecticides and the Nicotinic Acetylcholine Receptor. Tokyo Springer. 

Figure 4 Moiecuiar modeis of binding subsites in the Drosophila or vertebrate nicotinic acetyichoiine-reguiated receptors. (Reprinted with permission from Tomizawa etal. (2003) The neonicotinoid eiectronegative pharmacophore piays the cruciai roie in the high affinity and seiectivity for the Drosophila nicotinic receptor An anomaiy for the nicotinoid cation-pi interaction modei. Biochemistry 42 7819-7827 American Chemicai Society.)...

Kollmeyer WD, Flattum RE, Foster JP, et al. (1999) Discovery of the nitromethylene heterocycle insecticides. In Yamamoto I and Casida JE (eds.) Nicotinoid Insecticides and the Nicotinic Acetylcholine Receptor, ch. 3, pp. 71-89. Berlin Springer. 

Nicotine Derivatives. A large number of nicotine analogs have been reported, and the SAR of nicotine derivatives has been presented in a recent review by Tonder et al. (295). Described herein are two classes of nicotine derivatives 5-substituted nicotine analogs (e.g., SIB-1508Y, 51)and pyrrolidine ring-opened nicotinoids (e.g., RJR-2403,57). 

Pyrrilidine Ring-Opened Nicotin-oids. The nicotinoids, characterized as having an opened pyrrolidine ring, have been discussed in several reviews (273,293,295). Described herein is a series of trans-metanicotine analogs as nAChR agonists. 

Field dosages often span a very broad range, and the typical application rates , shown in Table 8.1, are for general comparison only. Nevertheless, these numbers indicate how field a.i. rates have decreased historically, as more active molecules have been developed examples include the neo-nicotinoid insecticides, triazole fungicides and sulfonylurea herbicides, which are one to two orders of magnitude more active than the early organochlorine, copper and aryloxyalkanoic acid pesticides, respectively. 

ACh receptor Atropine Antagonistic block, inhibiting transmission Paralysis, and reduces the effects of nicotinoids and ACh useful as an antidote against organophosphorus and carbamate poisoning... 

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. 

---