“From “There” to “Here””

… natural product templates (“there”), and how each template evolved through chemical structural modification that led either to optimized potency or unique psychopharmacology (“here”)

Transcript abstract

This talk will be an excursion that considers each of the major types of psychedelic agents: tryptamines, ergolines, and phenethylamines. The talk will feature natural product templates (“there”), and show how each template evolved through chemical structural modification that led either to optimized potency or unique psychopharmacology (“here”). Each chemotype has at some point in time been the focus of attention by natural products or medicinal chemists. For example, in the “modern” era, Western attention to psychedelics was first directed to mescaline, a simple trimethoxy-substituted phenethylamine produced by the peyote cactus, Lophophora wiliamsii. Anthropological studies have indicated the use of peyote by Native North Americans was ongoing as long as 5700 years ago. Following the identification of mescaline as the active component in peyote by Heffter in 1897, it was then synthesized in 1919 by Späth. More than four decades would then pass before the prodigious efforts of Alexander Shulgin led to a variety of ring-substituted analogues of mescaline. Part of Shulgin’s inspiration derived from his knowledge of the structures of essential oils. Additional medicinal chemistry efforts led to extremely potent congeners of mescaline. Similar, although less productive, studies occurred with simple tryptamines and with the tetracyclic ergolines. Each of these chemotypes will be discussed and it will be seen how natural products played a significant role in bringing psychedelics of various types to the present moment (“here”).