Discoveries and Challenges Encountered Towards the Development of a Metabotropic Glutamate Receptor 3 Positive Allosteric Modulator. Synthesis and Biological Evaluation of Hybrubin A. Synthesis of Natural and Unnatural Dibenzylbutane Lignans from a Shared Intermediate

Abstract

G-protein coupled receptors (GPCRs) are ubiquitous in drug development programs; one third of FDA approved therapeutics target GPCRs. Despite this, many GPCRs remain in obscurity as their exact physiological role in pathogenesis remains unclear. A particular class C GPCR, metabotropic glutamate receptor 3 (mGluR3), has been implicated in an array of neurological diseases. The first project focuses on the development of a small molecule positive allosteric modulator which could be used to probe the function of mGluR3 and provide evidence of this receptors role in central nervous system (CNS) disease states. Approximately two thirds of FDA approved small molecules have been in some manner inspired by natural products. Several techniques have emerged, such as combinatorial biosynthesis, which allow scientists to create “unnatural” natural products. One such material, Hybrubin A, has been synthesized and was profiled against a panel of discrete targets to discover a unique biological profile. Lignans represent an enormous class of natural products with multiple reported pharmacological benefits. One particular class of lignans, dibenzylbutanes, represent a chemical scaffold with high “drug-likeness”. This project established a robust chemical route to produce natural lignans and analogs thereof in high stereochemical purity. Such a synthetic route may inspire development of these lignans for biochemical studies.