https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

Over the course of the past half century, the structural elucidation of unknown natural products has undergone a tremendous revolution Before World War II, a chemist would have relied almost exclusively on the art of chemical synthesis, primarily in the form of degradation and derivatization reactions, to develop and test structural hypotheses in a process that often took years to complete when grams of material were available Today, a battery of advanced spectroscopic methods, such as multidimensional NMR spectroscopy and high-resolution mass spectrometry, not to mention X-ray crystallography, exist for the expeditious assignment of structures to highly complex molecules isolated from nature in milligram or sub-milligram quantities In fact, it could be argued that the characterization of natural products has become a routine task, one which no longer even requires a reaction flask! This Review makes the case that imaginative detective work and chemical synthesis still have important roles to play in the process of solving nature's most intriguing molecular puzzles

https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.200590046

Chasing molecules that were never there: misassigned natural products and the role of chemical synthesis in modern structure elucidation.

We assessed the pharmacological activity of anabaseine, a toxin found in certain animal venoms, relative to nicotine and anabasine on a variety of vertebrate nicotinic receptors, using cultured cells, the Xenopus oocyte expression system, contractility assays with skeletal and smooth muscle strips containing nicotinic receptors and in vivo rat prostration assay involving direct injection into the lateral ventricle of the brain. Anabaseine stimulated every subtype of nicotinic receptor that was tested. It was the most potent frog skeletal muscle nicotinic receptor agonist. At higher concentrations it also blocked the BC3H1 (adult mouse) muscle type receptor ion channel. The affinities of the three nicotinoid compounds for rat brain membrane alpha- bungarotoxin binding sites and their potencies for stimulating Xenopus oocyte homomeric alpha 7 receptors, expressed in terms of their active monocation concentrations, displayed the same rank order, anabaseine>anabasine> nicotine. Although the maximum currents generated by anabaseine and anabasine at alpha 7 receptors were equivalent to that of acetylcholine, the maximum response to nicotine was only about 65% of the acetylcholine response. At alpha 4- beta 2 receptors the affinities and apparent efficacies of anabaseine and anabasine were much less than that of nicotine. Anabaseine, nicotine and anabasine were nearly equipotent on sympathetic (PC12) receptors, although parasympathetic (myenteric plexus) receptors were much more sensitive to anabaseine and nicotine but less sensitive to anabasine. These differences suggest that there may be different subunit combinations in these two autonomic nicotinic receptors. The preferential interactions of anabaseine, anabasine and nicotine with different receptor subtypes provides molecular clues that should be helpful in the design of selective nicotinic agonists.

Anabaseine is a potent agonist on muscle and neuronal alpha-bungarotoxin-sensitive nicotinic receptors.

Chapter One - Alkaloids from Amphibian Skins

This invention relates to compositions for benzylidene- and cinnamylidene-anabaseines and methods for using these compositions for treating conditions associated with defects or malfunctioning of nicotinic subtypes brain receptors. These compositions target the alpha7 receptor subtype with little or no activation of the alpha4beta2 or other receptor subtypes.

Methods of use and compositions for benzylidene- and cinnamylidene-anabaseines

Two pyridine bases were isolated from the marine hoplonemertineAmphiporus angulatus (Fabricius) and identified by mass and PMR-spectroscopy as 2,3′-bipyridyl and 3,2′; 3′,2″; 4″,3′''-tetrapyridyl (Nemertelline). Nemertelline, the first tetrapyridyl natural product to be reported, shows a structural resemblance to the tobacco constituent nicotelline. The crustacean toxicity of 2,3′-bipyridyl is very similar to that of nicotine, but its mammalian toxicity is negligible.

J. H. Duncan

Papers

Hoplonemertine worms—a new source of pyridine neurotoxins