Nicotinic agonists toxicity

Other mechanisms, such as the inhibition of -amyloid formation. There are several other alkaloids which are nicotinic agonists at the cholinergic receptor such as lobeline (89) from Lobelia inflata. Lobelia inflata a could be exploited to influence cholinergic function in AD. Sophoramine (90) and cytisine (91), found in members of the Leguminosae, have nicotinic actions but they do not appear to have been developed for any pharmaceutical purposes, probably because of their toxicity. 

S. R., Hill, R. G. Antinociceptive and toxic effects of (+)-epibatidine oxalate attributable to nicotinic agonist activity, Br. J. Pharmacol. 1994, 113, 1487-1493. 

Pyrantel pamoate (Antiminth) is a agonist at the nicotinic acetylcholine receptor, and its actions result in depolarization and spastic paralysis of the helminth muscle. Its selective toxicity occurs primarily because the neuromuscular junction of helminth muscle is more sensitive to the drug than is mammalian muscle. This drug is administered orally, and because very little is absorbed, high levels are achieved in the intestinal tract. Less than 15% of the drug and its metabolites are excreted in urine. 

Bethanechol Muscarinic agonist t negligible effect at nicotinic receptors Activates Mi through M3 receptors in all peripheral tissues causes increased secretion, smooth muscle contraction (except vascular smooth muscle relaxes), and changes in heart rate Postoperative and neurogenic ileus and urinary retention Oral and parenteral, duration 30 min does not enter central nervous system (CNS) Toxicity Excessive parasympathomimetic effects, especially bronchospasm in asthmatics Interactions Additive with other parasympathomimetics... 

Succinylcholine Agonist at nicotinic acetylcholine (ACh) receptors, especially at neuromuscular junctions depolarizes may stimulate ganglionic nicotinic ACh and cardiac muscarinic ACh receptors Initial depolarization causes transient contractions, followed by prolonged flaccid paralysis depolarization is then followed by repolarization that is also accompanied by paralysis Placement of tracheal tube at start of anesthetic procedure t rarely, control of muscle contractions in status epilepticus Rapid metabolism by plasma cholinesterase normal duration, 5 min Toxicities Arrhythmias hyperkalemia transient increased intraabdominal, intraocular pressure postoperative muscle pain... 

Nomicotine, an organocatalyst studied by Dickerson and co-workers (Entry 5 [52, 58d], Appendix 7.B), reinforces the important principle that even catalysts from Nature can present problems when it comes to toxicity. The family of nicotinic receptor agonists (Figure 7.9) contains several chiral pyrrolidines and piperidines with the potential to act as asymmetric aldol catalysts. Nomicotine, which can be isolated from plants such as tobacco, or readily synthesized by demethylation of the maj or tobacco alkaloid nicotine, was investigated in some depth as an aldol catalyst by Dickerson and Janda in 2002 [52]. 

Epibatidine was shown to be a very potent and selective agonistic ligand of nicotinic acetylcholine receptors. This natural product is effective in various animal models of pain through a pronounced nAChR agonistic mechanism (Ki <100 pm) which is accompanied by severe and nACh-related side-effects (Corey et al. 1993 Rupniak et al., 1994 Boyce et al., 2000). A clear differentiation between antinociceptive activity in animal models of pain and toxic side-effects cannot be determined. Nevertheless there is some activity directed towards the development of epibatidine as an analgesic (Bai et al., 1997). 

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. 

Kihara T, Shimohama S, Akaike A (1999) Effects of nicotinic receptor agonists on beta-amyloid beta-sheet formation. Jpn J Pharmacol 79 393-396 Kihara T, Shimohama S, Sawada H, Honda K, Nakamizo T, Shibasaki H, Kume T, Akaike A (2001) alpha 7 nicotinic receptor transduces signals to phosphatidylinositol 3-kinase to block A beta-amyloid-induced neurotoxicity. J Biol Chem 276 13541-13546 Kihara T, Shimohama S, Urushitani M, Sawada H, Kimura J, Kume T, Maeda T, Akaike A (1998) Stimulation of alpha4beta2 nicotinic acetylcholine receptors inhibits beta-amyloid toxicity. Brain Res 792 331-334... 

The acute toxicity (i.e., lethal potency) of imidacloprid, other neonicotinoids, and related analogs in mammals is most closely related to potency at the 7 nicotinic receptor subtype, followed in order by potency at 1x4, fSx, 0(3, and aj nicotinic receptors, respectively. However, acute toxicity in mammals involves complex actions (agonist and antagonist) at multiple receptor subtypes and these actions vary greatly with minor changes in chemical structure. 

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... 

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. 

If ingested, QA exhibit a broad level of toxicity They interact with ACh receptors as agonists. QA, like many other alkaloids occur as complex mixtures in plants. We have shown recently [69], that some QA preferentially bind to the nicotinic AChR, whereas others tend more to... 

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