Small Molecule Allosteric Modulation of G Protein-Coupled Receptors and Applications in the Pharmacological Targeting of 5-HT2 Receptors

The discovery of G protein-coupled receptors (GPCRs) and the extensive second messenger systems associated with their activation has ushered in an enormously productive period in drug discovery. The extent to which around one-third of FDA-approved medications target GPCRs. Predictably, small molecule allosteric modulation has emerged in recent years as a new means to control GPCR function with numerous examples nearing FDA approval. This body of work begins with a substantive review of drug discovery efforts in the development of Class A GPCR allosteric modulators as a means to compile successful strategies and take note of the distinct challenges in the field as our group approaches allosteric modulator discovery for the serotonin 5-HT2C receptor (5-HT2CR). From the time of its characterization, the 5-HT2CR has been marked by unique, untapped potential as a drug discovery target for numerous diseases and disorders of the central nervous system. Thus, the second chapter in this work provides a clear rationale for 5-HT2CR allosteric modulator discovery in context of the neurobiological framework wherein the 5-HT2CR plays an integral role in reward-related behaviors and cortical executive functions. With the rationale established, the following sections report our efforts in the discovery of novel 5-HT2CR positive allosteric modulators (PAMs) from their design and chemical synthesis to the in vitro and in vivo characterization of these molecules. Additionally, further work describing 5-HT2CR PAM pharmacokinetic properties as suitable for rodent behavioral assays and the structural determinants of 5-HT2CR PAM binding via molecular modeling are discussed. Having discovered allosteric modulators with functionality across the 5-HT2R subfamily and benefiting from the wealth of available structural data for these targets, the final chapter delves into a theoretical mechanism underpinning allosteric modulation of 5-HT2Rs. The enhanced activation state (EAS) is thus coined for the first time herein to describe 5-HT2R PAM functionality and is treated with a rigorous theoretical framing comprised of the observed pharmacological, structural, and computational studies that shape our understanding of GPCR dynamics, specifically the activation dynamics of 5-HT2Rs. The resultant body of work provides the reader a comprehensive understanding of allosteric modulation and its pharmacological utility in targeting 5-HT2Rs.