{"id":{"repo_id":"utmb","oai_identifier":"oai:utmb-ir.tdl.org:2152.3/12078"},"canonical_url":"https://search.dev.ndltd.org/etd/utmb/oai:utmb-ir.tdl.org:2152.3/12078","repository":{"repo_id":"utmb","name":"University of Texas Medical Branch","base_url":"https://utmb-ir.tdl.org/server/oai/request"},"display":{"title":"Small Molecule Allosteric Modulation of G Protein-Coupled Receptors and Applications in the Pharmacological Targeting of 5-HT2 Receptors","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Wold, Eric A."],"institution":"The University of Texas Medical Branch at Galveston","degree_name":"Pharmacology and Toxicology (Doctoral)","degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2021,"date_issued":"2021-05-01T05:00:00.000Z","date_published":"2021-05-01T05:00:00.000Z","updated_at":"2026-07-24T05:50:56Z","subjects":["Chemistry, Pharmaceutical","Health Sciences, Pharmacology","Health Sciences, Toxicology"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2152.3/12078","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Wold, Eric A."]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2023-06-02T14:37:31Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2023-06-02T14:37:31Z"]},{"key":"dc:date.issued","label":"Date","values":["2021-05-01T05:00:00.000Z"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Pharmacology and Toxicology (Doctoral)"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["The University of Texas Medical Branch at Galveston"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Chemistry, Pharmaceutical","Health Sciences, Pharmacology","Health Sciences, Toxicology"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/2152.3/12078"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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."]},{"key":"dc:format.mimetype","label":"Dc Format Mimetype","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Small Molecule Allosteric Modulation of G Protein-Coupled Receptors and Applications in the Pharmacological Targeting of 5-HT2 Receptors"]}]}],"canonical_facts":{"dc:creator":["Wold, Eric A."],"dc:date.accessioned":["2023-06-02T14:37:31Z"],"dc:date.available":["2023-06-02T14:37:31Z"],"dc:date.issued":["2021-05-01T05:00:00.000Z"],"dc:description.abstract":["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."],"dc:format.mimetype":["application/pdf"],"dc:identifier.uri":["https://hdl.handle.net/2152.3/12078"],"dc:subject":["Chemistry, Pharmaceutical","Health Sciences, Pharmacology","Health Sciences, Toxicology"],"dc:title":["Small Molecule Allosteric Modulation of G Protein-Coupled Receptors and Applications in the Pharmacological Targeting of 5-HT2 Receptors"],"dc:type":["Thesis"],"thesis:degree_name":["Pharmacology and Toxicology (Doctoral)"],"thesis:institution_name":["The University of Texas Medical Branch at Galveston"]},"updated_at":"2026-07-24T05:50:56Z"}