The Calabar Bean and its Alkaloids

Investigations into Calabar beans (the dried ripe seeds of Physostigma venenosum) and their alkaloidal components compose a classical scientific journey throughout some one-and-a-half centuries and not only represent a fascinating aspect of the history of medicine but which is, moreover, still ongoing at the forefront of chemical and medical discovery. Those in particular involving its major such component, l-physostigmine, have led to an understanding of some of the fundamental mechanisms occurring in physiology, pharmacology and biochemistry and, either actually or potentially (by providing a template and thereby acting as a "lead compound") have provided a useful treatment for a variety of neurological disorders associated with irregularities in cholinergic transmission in which augmentation of cholinergic activity has proved to be beneficial. Physostigma venenosum  is distributed throughout equatorial West Africa and having a colourful history - by virtue of their former use as an ordeal poison in trials for witchcraft in the Efik society of Old Calabar - are its dried ripe seeds (Calabar beans). The major toxic compound isolated from these, l-physostigmine, which is also known as eserine and is the only alkaloid as yet also to be isolated from a microbial source (along with l-N(8)-norphysostigmine) and is the first alkaloid found to contain a 1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole ring system, and the first natural product found to contain a carbamyl group. It also became one of the first examples whereby the mechanism of action of a drug could be defined at the molecular level relatively simply, played a crucial role in the Nobel Prize - winning discovery of the mechanism of neurohumoral transmission, and has led to products for the treatment of a wide range of disorders associated with deficiencies in cholinergic transmission. Several other alkaloids have also been isolated from the Calabar bean. For some of these, structures have been established, syntheses effected and pharmacology investigated.