Design, synthesis and evaluation of fluorescent CB2 cannabinoid receptor ligands

Cannabis has been used as a medicinal and natural product for thousands of years. Whether it has been used to make rope or paper, or been used to treat pain or depression, cannabis has always had a place in human civilisation. \n\nWith the isolation of the psychoactive compounds responsible for cannabis’ effects, the discovery of two human cannabinoid receptors and an expanding knowledge of the therapeutic uses of cannabis, interest in the development of novel cannabinoids grew. The CB2 cannabinoid receptor has gained particular attention, as the often unwanted central and psychoactive effects of cannabinoids has been attributed to the CB1 cannabinoid receptor. Development of CB2 receptor selective ligands offers treatment opportunities in many areas, but most especially for pain, multiple sclerosis and immunomodulation.\n\nThe preparation of fluorescently labelled ligands for a variety of receptors has improved compound screening techniques, as well as allowing use as biomolecular probes for aiding our understanding of the receptor in situ. The aim of this work is to design, synthesise and evaluate novel fluorescently labelled cannabinoids, with a particular interest in CB2 selective compounds.\n\nFocusing on the CB2 receptor selective alkylindole JWH-015, targeted substitutions were made to its naphthyl ring to identify sites that might be suitable for fluorophore attachment. With a site chosen, a series of fluorescent JWH-015 analogues was synthesised and evaluated for their CB2 receptor binding affinities. Though none of the evaluated compounds showed sufficient binding affinity for them to be used as biomolecular tools, the structure activity relationships gained suggested that improved design of fluorescent JWH-015 analogues in future could lead to the first ever active fluorescent cannabinoid.