Doctor of Philosophy (PhD)
The G protein regulated inwardly rectifying potassium channels (GIRK) are a family of inwardly rectifying potassium channels and are key effectors in signaling pathways. GIRK 1/2 channel subunit, predominantly found in the brain, is involved pathophysiology of various neurological disorders including, but not limited to, epilepsy, anxiety, Parkinson's, pain, reward, and addiction. Previously, our laboratory had identified a series of urea containing molecules as GIRK1/2 preferring activators. Unfortunately, the urea series suffers from significant PK liabilities (solubility, brain penetration and high clearance). The chapter 1 of the dissertation describes our efforts in developing three new series of activators with improved pharmacokinetics properties while retaining activity. Human Mas-related G protein-coupled receptor X1 (MRGX1) is a part of the larger GPCR family of receptors and has restricted expression in nociceptors within the peripheral nervous system. Allosteric activation of Mrgx1 inhibits the high voltage acting Ca2+ (HVA) channel necessary for nociception. This makes it a promising target for non-addictive pain therapy. Previous efforts in our lab for optimization of hits obtained from high-throughput screening (HTS) had led to the development of a selective MrgX1 allosteric agonist, ML382. Chapter-2 shows our SAR studies around ML382 to overcome potential pharmacokinetic liabilities of ML382 and identify newer and more potent MrgX1 allosteric agonists. Through our medicinal chemistry based efforts we were able to identify 10 fold more potent agonists compared to ML382. Progressive chronic kidney disease (CKD) is characterized by a total or considerable loss in kidney function, affects approximately 1 in 10 people around the world. Previous work in our collaborator's laboratory has established the role of the transient receptor potential canonical-5 (TRPC5) ion channel in mediating calcium influx in podocyte leading to cytoskeletal changes and loss of functionality. Chapter-3 describes our medicinal chemistry based approach for the design, synthesis and characterization of novel benzimidazole basedTRPC5 inhibitors We were able to bring the activity from micro-molar to low nano molar.
Sharma, Swagat H., "Design and Synthesis of Small Molecular probes for CNS and Kidney Disorders" (2021). Theses & Dissertations. 583.
Available for download on Monday, May 02, 2022