[Storm Shadow]

https://etheses.nottingham.ac.uk/712/...s_Holt_PhD.pdf

Abstract

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.
With 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 CB

2 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.
The 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.
Focusing 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.