This presentation will chronicle selected aspects of an unpredictable journey that began with solving a problem in the synthesis of a natural product. This discovery not only led to a general new strategy for alkaloid synthesis, but it inspired the development of a general platform that may be used for the rapid assembly of diverse nitrogen heterocycles and natural product mimics. Prospecting with selected members of these collections against proteins in the central nervous system led to the discovery of novel compounds that selectively bound to the sigma 2 receptor (σ2R), an enigmatic protein whose structure and function were unknown. Exploring the biological effects of σ2R ligands led to the identification of σ2R as transmembrane protein 97 (σ2R/TMEM97). More importantly, we discovered that selective modulation of σ2R/TMEM97 with small molecules has beneficial effects in models of several neurodegenerative diseases and neurological disorders, thereby opening the door to possible treatments for unmet medical needs in neuroscience by a new mechanism of action.

Bridging unknown unknowns: From natural products to unmet needs in neuroscience

ACS Spring Meeting 2021

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