Bioactive compounds from Cannabis sativa have been used for millennia to alleviate the symptoms of a range of diseases. The physiological basis of effects such as analgesia, stimulation of hunger and reduction of inflammation was established in the late 20th century with the discovery of cannabinoid receptors but efforts to synthesise safe and potent drugs targeting these proteins have so far failed. The major barrier to research in this area is the instability of the receptors outside of biological settings, rendering elucidation of the binding sites by traditional means difficult. Certain small molecules can interact with the cannabinoid type 1 receptor (CB1) at locations distinct to the primary ligand docking site. Such allosteric modulation of the endocannabinoid system offers significant advantages over using orthosteric drugs and in this research a range of indole based structures were synthesised and tested in an attempt to improve the activity and drug-like nature of a lead compound. A partial structure-activity relationship was established, including the description of the most potent allosteric enhancer of CB1 so far reported. Efforts were also undertaken to investigate the allosteric binding environments using photoactivatable ligands based on a CB1 inhibitor. In combination with mutation studies and computer modelling this technique could allow the rational design of allosteric modulators, a task which is not trivial at present. Two photoactivatable compounds were synthesised and shown to interact with the receptor, with a method for isolating covalently labelled peptide fragments from other biomolecules demonstrated using “click chemistry” and a modified Wang resin. This work may find application in future investigations aiming to produce allosteric pharmaceuticals targeting CB1. Furthermore, the techniques described may be applied to study the binding site of a recently described allosteric endocannabinoid or could potentially be adapted to look at secondary binding domains in other G protein-coupled receptors.

Thesis (Ph. D.)--University of Washington, 2004. / Vita. Includes bibliographical references (leaves 93-112).

Thesis (Ph.D.)--Virginia Commonwealth University, 2010. / Prepared for: Dept. of Pharmacology and Toxicology. Title from title-page of electronic thesis. Bibliography: leaves 109-123.