Measuring drug concentrations where it matters: the influence of subcellular ligand distribution on cellular pharmacology
Lead Research Organisation:
University of Nottingham
Department Name: School of Life Sciences
Abstract
When the pharmacology of new drugs is assessed it is assumed that the concentration of drug that the receptor is exposed to is the same as that in bulk aqueous phase. Lipophilic and/or basic drugs can, however, interact directly with the membrane surrounding the receptor, potentially concentrating drug close to the receptor. This rotation project will use cutting-edge biophysical imaging techniques to quantify the local drug concentrations of two fluorescent adenosine A1 receptor (A1-AR) ligands with different physicochemical properties to assess whether non-specific membrane interactions influence observed receptor pharmacology.
Fluorescence correlation spectroscopy (FCS) is a microscopy technique that measures fluctuations in fluorescence intensity from a small (~0.2fL) defined confocal volume, allowing both diffusion time and concentration to be determined for a fluorescent compound. The FCS detection volume will be positioned at various heights above the plasma membrane of cells expressing the A1-AR to measure the concentration of drug close to the receptor and in bulk aqueous phase. These concentrations will be compared to existing pharmacological data to determine whether differences observed can be related to their different physicochemical properties and subsequent concentration in the local vicinity of the receptor.
Fluorescence correlation spectroscopy (FCS) is a microscopy technique that measures fluctuations in fluorescence intensity from a small (~0.2fL) defined confocal volume, allowing both diffusion time and concentration to be determined for a fluorescent compound. The FCS detection volume will be positioned at various heights above the plasma membrane of cells expressing the A1-AR to measure the concentration of drug close to the receptor and in bulk aqueous phase. These concentrations will be compared to existing pharmacological data to determine whether differences observed can be related to their different physicochemical properties and subsequent concentration in the local vicinity of the receptor.
Organisations
People |
ORCID iD |
Steven Charlton (Primary Supervisor) |
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
BB/M008770/1 | 30/09/2015 | 31/03/2024 | |||
1803186 | Studentship | BB/M008770/1 | 30/09/2016 | 02/12/2020 |
Description | Speaking to Patient group about research |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | During the rotation period of my BBSRC-DTP I visited a patient support group of approximately 20-30 people with one of my rotation supervisors. The purpose was to gain perspective from patients that might ultimately benefit from the laboratory work. Also to give the patients an insight into the work we were doing. |
Year(s) Of Engagement Activity | 2017 |