| dc.description.abstract | Herein, we first describe the discovery of the first inhibitor of the inward rectifying potassium channel 4.1/5.1 (Kir4.1/5.1) heterotetramer, VU6036720. The potency and selectivity of VU’720 was established using fluorescence‐ and electrophysiology‐based assays, and this novel class of compounds can now be leveraged for exploring the integrative physiology and therapeutic potential of Kir4.1/5.1 channels in diseases associated with dysfunction of Kir4.1‐containing channels. Also described, is the development of a novel metabotropic glutamate (mGlu) receptor 4 positive allosteric modulator (PAM) with a novel chemotype. Several mGlu4 PAM in vivo tool compounds have been reported in literature, offering evidence that mGlu4 PAMs serve as promising, disease-modifying treatment for Parkinson’s disease. The disclosed compound, VU6022296, was developed from a micromolar lead from a high throughput assay to be a potent, brain-penetrant mGlu4 PAM with in vivo antiparkinsonian efficacy. Finally, the synthetic efforts towards the total synthesis of Thiocladospolide A are described. Thiocladospolide A is a newly disclosed sulfur-containing metabolite from of the mangrove-derived fungal strain Cladosporium cladosporioides (MA-299). Thiocladospolide A exhibits activity against Gram-positive and Gram-negative bacteria. Considering the potential therapeutic potential, attractive molecular structure, and lack of existing syntheses, a concise synthesis of Thiocladospolide A was attempted. | |
