CHALLENGES IN THE DISCOVERY AND OPTIMIZATION OF MGLU2/4 HETERODIMER POSITIVE ALLOSTERIC MODULATORS AND TOTAL SYNTHESIS OF EPI- AND PERICOANNOSIN A

Abstract

The metabotropic glutamate receptor 2/4 (mGlu2/4) heterodimer is a recently discovered receptor that displays unique pharmacology with respect to both mGlu2 and mGlu4 homodimeric receptors. Additionally, in vivo work has shown that these receptors may be localized to corticostriatal synapses, a region of the brain associated with behavior gating and impulse control. Modulation of this receptor with positive allosteric modulators (PAMs) could potentially be therapeutic for the amelioration of certain symptom clusters observed in schizophrenia. More than 500 PAMs across a diverse set of more than 13 chemical scaffolds revealed no scaffold that displayed selectivity for the heterodimeric receptor over both homodimers. Additionally, a number of false positives were discovered that directly activated the G protein-coupled inward rectifying potassium (GIRK) channels used in the thallium flux assay that was used measure mGlu2/4 activation. Next, the synthesis of bivalent tethered ligands, derived from two PAMs shown to have additive effects at the heterodimer was accomplished. These were synthesized using linkers of various lengths to attempt to achieve the ideal spacing for binding to both allosteric pockets in the mGlu2/4 heterodimer. While the data in our assays were complicated, data obtained from heterodimer selective signaling assays in collaboration with the Javitch lab confirmed that the tethered ligands were active at both homodimers, but were unable to potentiate at the heterodimers for reasons that are still being explored. The total synthesis of the fungal metabolite Pericoannosin A and an epimer was accomplished in an efficient 12 linear step, 19 overall step sequence, with marked improvements over the published synthesis that achieved the final product in 18 linear steps and 23 total. Highlights of this synthesis include an asymmetric Diels-Alder that helps to set all of the stereocenters in the natural product and a one-pot Staudinger reduction/lactam cyclization sequence.