Graham B. Jones, Jack Bergman, Zhaohui S. Zhou
Date of Award
Doctor of Philosophy
Department or Academic Unit
College of Science. Department of Chemistry and Chemical Biology.
chemistry, cannabinoid receptors, biaryl ether, biaryl analogs, receptor ligands
G proteins, Ligands
Two cannabinoid receptors (CB1 and CB2) belonging to the superfamily of G-protein coupled receptors (GPCRs) play a vital role in multiple physiological functions. CB1 is found primarily in the central nervous system (CNS) and CB2 in the periphery. Those compounds that bind to these receptors, irrespective of their structure, are considered cannabinoids. It is because of the widespread receptor distribution and its potential therapeutics that this is an attractive receptor target.
It is the purpose of this work to explore the structural modifications of biaryl ether and biaryl analogs as cannabinoid receptor ligands. Chapter One introduces the relevant background information on the biology, structure and physiology of cannabinoid receptors, ligands, and their therapeutic potential. An overview of the current state of the cannabinoid field is presented.
Chapter Two describes the Structure Activity Relationship studies (SARs) exploring the biaryl ether structure of BAY-59-3074, a novel partial agonist of the CB1/2 receptors. Here the rationale and design of the project is presented. Chapter Three further expands on the SAR of BAY59-3074 by exploring the conformational requirements for CB receptor binding and activation. A series of novel constrained dibenzofuran and dibenzopyran analogs were synthesized using the strategy of conformational restriction as a tool for molecular modification and design. These two chemotypes provide new leads for the development of CB2-selective cannabinergics.
Chapters Four and Five expand further on key compounds identified in Chapter Two. Chapter Four explores the biphenyl structure as CB2 receptor ligands. Chapter Five examines biaryl analogs as inhibitors of the endogenous deactivating protein Fatty Acid Amidase Hydrolase (FAAH).
Lastly, Chapter Six evaluates future directions for continuing investigations into the biaryl ether and biaryl cannabinoid templates. Here we discuss the future of CB therapeutics without CNS effects and consider future work.
Teng, Heidi, "Biaryl ether and biaryl analogs as cannabinoid receptor ligands" (2011). Chemistry Dissertations. Paper 32. http://hdl.handle.net/2047/d20001155
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