Structure anatoxin

Brough, E, Thomas, E, Gallagher, T, and Wonnacott, S. 1994. Anatoxin structure-activity studies. Synth Chem 246-248. 

Figure 1. Structure of (+)-anatoxin-a and two analogs with agonist and noncompetitive antagonist activity, respectively.

Figure 1. Structure of anatoxin-a from Anabaena flos-aquae NRC-44-1, saxitoxin and neosaxitoxin. Saxitoxin and neosaxitoxin is produced by certain species of marine algae and by the freshwater cyanobacteria Aphanizomenon flos-aquae NH-5.

Fig. 16.2. Chemical structure of anatoxin-a(s). This image is licensed under the http //www.gnu.org/copyleft/fdl.html GNU Free Documentation License. It uses material from the http //en.wikipedia.org/wiki/Cyanotoxin Wikipedia article.

Anatoxin-a is a toxic alkaloid occurring in the filamentous blue-green alga Anabaena flos-aquae and has been responsible for fatalities amongst livestock and wildlife. Mass and n.m.r. spectroscopy, and X-ray diffraction analysis of its N-acetyl derivative, pointed to structure and absolute stereochemistry (12) for ana-... 

Anatoxin-a, the first highly potent cyanotoxin to have its structure and absolute stereochemistry elucidated, was originally isolated from a unialgal clone of Anabaena Jlos-aquae (NRC-44h) [5]. The structure was confirmed by X-ray crystallographic data for the N-acetyl derivative [11] and additional studies have since provided further proof for the structure and stereochemistry (for example, [12]). Anatoxin-a is an unsymmetrical bicyclic secondary amine, and was the first naturally occurring alkaloid discovered to contain a 9-azabicyclo[4,2,l]nonane (homotropane) skeleton. Homotropanes are one-carbon analogs of the tropanes and, as such, are structurally closely related to the well-known alkaloid cocaine. 

The unique structure of anatoxin-a, and its potential as a pharmacological tool, has inspired many different chemical syntheses of anatoxin-a and analogs. The earliest synthesis, in 1977, used (—)-cocaine as starting material [23]. Subsequently, there... 

The SARs of anatoxin-a and analogs have been extensively studied [33-36], and only a few important findings dealing with chirality, conformation, and other structural features of anatoxin-a and homologs vfill be summarized here. A recent review that addresses the chemistry and pharmacology of anatoxin-a and analogs provides a more detailed treatment of this topic [37]. 

As compared to the natural ligand ACh, the conformation of anatoxin is relatively rigid, with only one rotatable bond as compared to four in ACh. This simplifies the ability to correlate the structural conformation of the ligand to efficacy, and, consequently, attention has been directed toward determining the active conformation through the use of sterically constrained analogs of the s-ds and s-trans conformers of anatoxin-a [19,40-44]). Although current evidence leans toward s-trans as the active conformation, condusive evidence, such as a crystal structure of (+)-anatoxin-a in complex with an nACh receptor, is still needed. 

Anatoxin-a(s) is produced in both Anabaena flos-aquae [56] and Anahaena lemmer-mannii [57]. The symptoms of anatoxin-a(s) intoxication are similar to those of anatoxin-a but cause increased salivation in vertebrates hence, the similarity in the names of these compounds with the (s) added to indicate salivation [18]. The structures, however, are quite different, as are the mechanisms of action. 

Until recently, anatoxin-a was the only naturally occmring alkaloid possessing the 9-azabicy-clo[4.2.1]nonane ring skeleton, in contrast with the many examples of the similar 8-azabicy-clo[3.2.1]octane ring systems found in the diverse and widely distributed atropine alkaloids (i.e., ferruginine and cocaine). As a result of the combination of its biological potency and its rare structure,... 

One of the most popular methods for creating the anatoxin-a skeleton is by transannular cyclization of a suitably substituted cyclooctene. This approach was used in the first synthesis of racemic anatoxin-a (Campbell et al. 1979). They carried out two different methodologies in order to reach the 9-azabicyclo[4.2.1]nonane structure (Scheme 7.3). The 1,5-cyclooctadiene (10) starting compound was transformed into the methyl amine 11 which was treated with hypobromous acid to produce the desired bicycle 12 as a mixture of diastereoisomers in 29% overall yield, with some amount of the azabicyclo[3.2.1] analogue (Bastable etal. 1972). 

Anatoxin-a is a useful core structure for nicotinic drug design. For this reason, synthetic approaches to anatoxin-a are still active research areas, open to new proposals, and the search for new analogues that would act like drugs in the treatment of brain disease is still an important task in medicinal chemistry (Breiiung 2004). 

Brough, RA., Gallagher, T., Thomas, P., Wonnacott, S., Baker, R., Abdul Malik, K.M., and Hursthouse, M.B. 1992. Synthesis and X-Ray crystal structure of 2-acetyl-9-azabicyclo[4.2.1]nonan-3-one. A conformationally locked s-cis analogue of anatoxin-a. J Chem Soc Chem Commun 1087-1089. 

Huby, N.J.S., Thompson, P, Wonnacott, S., and Gallagher, T. 1991. Structural modification of anatoxin-a synthesis of model affinity ligands for the nicotinic acetylcholine receptor. J Chem Soc Chem Commun 243-245. 

Swanson, K.L., Aronstam, R.S., Wotmacott, S., Rapoport, H., and Albuquerque, E.X. 1991. Nicotinic pharmacology of anatoxin analogues. 1. side-chain structure-activity-relationships at peripheral agonist and noncompetitive antagonist sites. 

Figure 8.2. Structures of (A) anatoxin-a(s) and (B) its main degradation product.

In 1993, as ABT-418 progressed through the course of early clinical trials, the pressing mission of the medicinal chemistry group was to prepare potential backup compounds. A matter of some debate was whether another isoxazole-like compound should suffice as a backup, or whether an entirely different series needed to be identified. A number of known nAChR ligands with diverse structures, such as anatoxin-a (5), l,l-dimethyl-4-phenylpiperazinium (6), and iV-methylcarbamyl choline (7), could potentially serve as lead compounds, and indeed many of these, as well as numerous isoxazole variants, were explored to at least some degree. 

Anatoxin-a(s) (61) is a potent neurotoxin, first isolated from the cyanobacterium A. flos-aqmeP Despite the name of this metabolite, it is structurally unrelated to anatoxin-a (62). The structure was not solved until 1989 through a combination of H, and NMR experiments on a sample of anatoxin-a(s) that had been... 

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