The Design of Anticholinesterases

The significance of new findings in two areas will be discussed with respect to the design of inhibitors of acetylcholinesterase. One area is that of enzyme structure, including the oligomeric form and the existence of allosteric binding sites, of isozymes and of a mutant enzyme. The other area is that of the forces which bind inhibitors to the enzyme prior to reacting with it, including ionic, hydrophobic and charge-transfer bonds. Now that the chlorinated hydrocarbon insecticides are being phased out in so many parts of the world, because of environmental considerations, the carbamates and phosphates, which together make up the group which we call anticholinesterase insecticides, have come to dominate the insecticide scene. This diverse group of compounds has a number of interesting features. For instance, both the potency and the hazard vary over great extremes, all the way from the nerve gases to highly selective compounds which are almost entirely safe to man and livestock. It is not at all difficult to synthesize an entirely new anticholinesterase, for there is a tremendous diversity of permitted attachments to the basic carbamyl or phosphoryl group. Many of these new compounds would have useful insecticidal properties The problem is to develop compounds which are of modest price, excellent potency and appropriate safety to man, livestock and the environment. But since so many useful anticholinesterase insecticides are in existence already, what are the prospects for obtaining compounds new and interesting enough to encourage the substantial research outlays which are necessary for any new compound? My own view is that we have only just begun to scratch the surface. Firstly, using the toxicity to vertebrates as an index of bioactivity, it is well known that the chemical warfare agents sarin and soman, which are anticholinesterases, are about 100 times more toxic than any of the organophosphates that are or were in commercial use. Secondly, insects can certainly be killed by different kinds of nerve poisons acting at extraordinarily low doses, as the exciting work on synthetic pyrethroids related to bioresmethrin has shown. One has a lethal dose for the housefly of 13 ng/g, or about 60 times more toxic than the best of the current commercial anticholinesterases. It seems to me entirely reasonable to set our sights upon the achievement of anticholinesterases which are about 100 times more toxic than current