Onchidals

Applying this strategy, the authors [10] suggested investigation of the origin of triophamine (112) in the nudibranch Triopha catelinae [164], of onchidal (113)... 

Abramson, S. N., Radic, Z., Manker, D., Faulkner, D. J., and Taylor, P., Onchidal a naturally occurring irreversible inhibitor of acetylcholinesterase with a novel mechanism of action, Mol. Pharm., 36, 349, 1989. 

Onchidal and fasciculins are natural toxins, which produce their toxicity in mammalian systems by virtue of primarily acetylcholinesterase (AChE) inhibition. AChE hydrolyzes and inactivates acetylcholine, thereby regidating the concentration of the transmitter at the synapse. Termination of activation is normally dependent on dissociation of acetylcholine from the receptor and its subsequent diffusion and hydrolysis, except in diseases where acetylcholine levels are limiting or under AChE inhibition, conditions that increase the duration of receptor activation (Silver, 1963). 

One of the first interesting structures with cholinergic properties isolated from a marine source is the chemical onchidal. This compound was first isolated from the mollusc Onchidella binneyi and has an acetate ester similar to acetylcholine. Upon isolation, onchidal was discovered to be an active site-directed irreversible inhibitor of AChE (Abramson et ah, 1989). 

Onchidal is a toxic component of a certain poisonous marine opisthobranch mollusc. Like other opisthobranchs, the Onchidiacea family of molluscs does not have the protection of a hard external shell as do most molluscs. They rely instead on the production of a defensive secretion. When the animal is disturbed it secretes a viscous fluid from specialized glands. In two species of Onchidella Onchidella Jhr-idanun and Onchidella borealis), this defensive secretion has been shown to act as a deterrent to potential predators, including fish and crabs. Chemically, it is a simple lipophilic acetate ester (see Figure 11.1). 

TABLE 11.1. Concentration of onchidal in different species of Onchidella (Abramson et al., 1989)... 

Organism Collection site Onchidal concentration ( tg/animal)... 

The structural similarity between onchidal (an acetate ester) and acetylcholine suggested that the toxicity of onchidal could result from inhibition of either nicotinic acetylcholine receptors or AChE. Although onchidal (1.0 mM) did not prevent the binding of 1-a-bungarotoxin to nicotine acetylcholine receptors, it inhibited AChE in a progressive, apparently irreversible, manner. The apparent affinity of onchidal for the initial reversible binding to AChE (Kd) was approximately 300 p.M, and the apparent rate constant for the subsequent irreversible inhibition of enzyme activity (Xij ct) was approximately 0.1 min ... 

Onchidal is an irreversible inhibitor of enzyme AChE with a novel mechanism of action. It has been suggested, however, that its toxicity could be a consequence of the inhibition of either nicotinic acetylcholine receptor or AChE enzyme. 

Incubation of AChE with onchidal resulted in the production of acetate, demonstrating that onchidal was a substrate for AChE, and approximately 3250 mol of onchidal was hydrolyzed/mol of enzyme irreversibly inhibited. Organophosphate and carbamate inhibitors of AChE have partition ratios (mol of toxin hydrolyzed/mol of enzyme irreversibly inhibited) that approach unity. Therefore, the relatively high partition ratio for onchidal suggests that the mechanism of inhibition utilized by onchidal may be distinctly different from other irreversible inhibitors (Walsh, 1984). The rate of hydrolysis of onchidal (Acat) was 325 min this value is relatively slow suggesting that onchidal is not a very good substrate. The ability of AChE to hydrolyze onchidal raised the question of whether inhibition of enzyme activity resulted from onchidal itself or from a product of the enzymatic hydrolysis of onchidal. Enzyme kinetics revealed that onchidal was unable to completely inhibit higher concentrations of AChE. From the experiments performed by Abramson et al. (1989), onchidal was in molar excess and was completely hydrolyzed. Thus,... 

The results summarized in Table 11.3 show that the software DfW identified the a, 3-unsaturated aldehyde moiety on onchidal as a structural alert and predicted this reactive center of the molecule to possess bacterial (Salmanella typhimurium) mutagenic potential at the reasoning level the software defines as plausible . Plausible is an uncertainty term in the software s reasoning tree and is defined as The weight of evidence supports the proposition (Marchant et al., 2008). The prediction of mutagenicity for the a,P-unsaturated aldehyde moiety on... 

TABLE 11.3. Summary of in silica predictive toxicological evaluations of onchidal by Derek for Windows and MDL-QSAR... 

FIGURE 11.3. The Derek for Windows version 10.0.2 (DfW) prediction for onchidal under default processing contraints. 

FIGURE 11.4. The MDL-QSAR version 2.2.2.0.7 prediction for mutagenic potential of onchidal in Salmonella typhimurium. 

The natural toxins onchidal and fasciculins behave as anti-ChE agents. Onchidal is an active site-directed irreversible inhibitor of AChE, and fasciculins are proteinic AChE inhibitors which bind to a peripheral regulatory anionic site of AChE in a noncompetitive and irreversible manner. 

There is limited information about the toxicity, toxicokinetics, and toxicological properties of onchidal and additional data are needed to make a health effects-based risk assessment of the natural compound. Although fasciculins are much better known, data on toxicological properties and toxicokinetics will be of interest and usefiil for risk assessments despite it being generally accepted that the toxicity of this proteinic toxin occurs at very low doses. 

Onchidal and fasciculins are interesting natural compounds and it is difficult to predict their toxicity. In the case of onchidal, in silico computational predictive modeling for toxic endpoints of interest may prove useful for risk assessment decision support. Likewise, it is a challenge to predict the mditary potential and human impact of these natural toxins since their affinity for enzyme inhibition depends upon the amount and duration of the human exposure. 

Neurotransmitter inactivation. A number of animal and plant agents act as ANTICHOLINESTERASES, so interfering with synaptic trasmission. These include fasciculins (Fasl, Fas2, FasS), which are peptide snake venoms, huperzine from a plant, onchidal from molluscs and physostigmine (eserine) from the calabar bean. 

Onchidal (265) is the principal constituent of a secretion of glands of amollusk (334). This... 

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