Fluorescent cannabinoids: Stratagies towards the synthesis of fluorescently labelled CB2 receptor ligands

Yates, Andrew Stephen (2005) Fluorescent cannabinoids: Stratagies towards the synthesis of fluorescently labelled CB2 receptor ligands. PhD thesis, University of Nottingham.

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Abstract

An increased understanding of the peripheral cannabinoid receptor (CB2) is required due to the CB2 receptor's emerging involvement in a number of disease states. New fluorescent technologies are capable of generating information about the CB2 receptor systems that has been unachievable using existing pharmacological methods i.e. radioisotope techniques.



Our work, to develop fluorescently labelled CB2 receptor ligands, will provide cannabis researchers a unique pharmacological tool to use in conjunction with these emerging fluorescent technologies. This will aid the understanding of cellular actions of cannabinoids and accelerate the discovery of novel CB2 selective drugs.

We report on the design, synthesis, and biological evaluation of novel fluorescent ligands targeted towards the CB2 receptor. The fluorescent ligands were designed and synthesised by conjugating recognized high affinity selective CB2 ligands (JTE2-3, JTE2-6 & JWH015) to appropriate fluorescent dyes via a chemical linker. Positioning of the fluorescent dye upon the pharmacophore was guided using established SAR data and supplemented by in-house molecular modelling experiments.

Our results showed that modification of JTE2-3 and JTE2-6 with dansyl and BODIPY fluorophores resulted in fluorescent ligands which displayed poor affinity to the CB2 receptor and consequently were unsuccessful when used in fluorescent confocal microscopy experiments. Furthermore, our studies revealed important species selectivity, associated with JTE2-3, which was previously unrecognised.

Using de novo drug design on JWH015, we synthesised and tested a 3-naphthyl modified fluorescent conjugate, 3-Gly-NBD-JWH015. The compound retained limited affinity to the CB2 receptor, but fluorescent confocal microscopy did not reveal specific receptor membrane binding. Further experiments using 3-naphthyl precursor compounds, displaying less bulky 3-substituents, demonstrated that limited modification to the 3-naphthyl position of JWH015 was tolerated and provided a first insight to the SAR at this position.

Item Type:Thesis (PhD)
Supervisors:Kellam, Barrie
Kendall, David
Chan, Weng
Doughty, Stephen
Uncontrolled Keywords:cannabis, CB2, fluorescent ligands, BODIPY, JWH015, molecular modelling, cannabinoid, medicinal chemistry, Japan Tobacco, CB1
Faculties/Schools:UK Campuses > Faculty of Science > School of Pharmacy
ID Code:107
Deposited By:Andrew Stephen Yates
Deposited On:11 Jul 2005
Last Modified:06 Feb 2009 14:43

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