Drug metabolism and pharmacokinetics in the lead optimisation of novel positive allosteric modulators of α1 strychnine sensitive glycine receptors

Wylde, Elinor (2015) Drug metabolism and pharmacokinetics in the lead optimisation of novel positive allosteric modulators of α1 strychnine sensitive glycine receptors. PhD thesis, University of Liverpool.

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Abstract

Chronic pain is a condition that is thought to affect roughly 8 million people in the UK. It is classified as pain that persists for more than 6 months. Chronic pain is commonly associated with depression, insomnia, anxiety and poor quality of life. Many treatments for chronic pain are accompanied by numerous debilitating side-effects, this in combination with insufficient pain relief means that approximately 50% of patients will discontinue their treatment. Most sufferers choose to live with the pain rather than deal with numerous adverse-effects. There is a great need for new therapeutics that are specifically designed to target the underlying mechanisms of chronic pain, therefore providing safer and more effective treatments. One such mechanism is the down-regulation of strychnine-sensitive glycine receptors (SSGRs) localised in the dorsal horn. Glycinergic activity is known to be inhibitory and artificial stimulation can produce analgesia. Positive allosteric modulators acting on α1 SSGRs may able to compensate for the inhibitory glycinergic activity that is reduced in chronic pain. Previous work within the group lead into the identification of propofol analogues designed to be novel positive allosteric modulators of α1 SSGRs. Work presented in this thesis describes the generation and optimisation of these analogues with a focus of drug metabolism and pharmacokinetics. The hit to lead process has resulted in the development of a lead compound that is highly potent at the target, has excellent pharmacokinetic and safety profiles and is able to produce high levels of analgesia in an animal model of neuropathic pain.

Item Type:	Thesis (PhD)
Additional Information:	Date: 2015-10 (completed)
Subjects:	?? QP ?? ?? RS ??
Divisions:	Faculty of Health and Life Sciences
Depositing User:	Symplectic Admin
Date Deposited:	06 Sep 2016 10:07
Last Modified:	17 Dec 2022 02:11
DOI:	10.17638/02048099
URI:	https://livrepository.liverpool.ac.uk/id/eprint/2048099