Journal article
Positive Allosteric Modulators of Glycine Receptors and Their Potential Use in Pain Therapies
Pharmacological Reviews, Vol.74(4), pp.931-959
2022
PMCID: PMC9553105
PMID: 36779343
Abstract
Glycine receptors are ligand-gated ion channels that mediate synaptic inhibition throughout the mammalian spinal cord, brainstem, and higher brain regions. They have recently emerged as promising targets for novel pain therapies due to their ability to produce antinociception by inhibiting nociceptive signals within the dorsal horn of the spinal cord. This has greatly enhanced the interest in developing positive allosteric modulators of glycine receptors. Several pharmaceutical companies and research facilities have attempted to identify new therapeutic leads by conducting large-scale screens of compound libraries, screening new derivatives from natural sources, or synthesizing novel compounds that mimic endogenous compounds with antinociceptive activity. Advances in structural techniques have also led to the publication of multiple high-resolution structures of the receptor, highlighting novel allosteric binding sites and providing additional information for previously identified binding sites. This has greatly enhanced our understanding of the functional properties of glycine receptors and expanded the structure activity relationships of novel pharmacophores. Despite this, glycine receptors are yet to be used as drug targets due to the difficulties in obtaining potent, selective modulators with favorable pharmacokinetic profiles that are devoid of side effects. This review presents a summary of the structural basis for how current compounds cause positive allosteric modulation of glycine receptors and discusses their therapeutic potential as analgesics.
Details
- Title
- Positive Allosteric Modulators of Glycine Receptors and Their Potential Use in Pain Therapies
- Authors
- Casey I. Gallagher (Author) - The University of SydneyDamien A. Ha (Author) - The University of SydneyRobert Harvey (Author) - University of the Sunshine Coast, Queensland, School of Health and Behavioural Sciences - LegacyRobert J Vandenberg (Author) - The University of SydneyLynette Daws (Author)
- Publication details
- Pharmacological Reviews, Vol.74(4), pp.931-959
- Publisher
- American Society for Pharmacology and Experimental Therapeutics
- Date published
- 2022
- DOI
- 10.1124/pharmrev.122.000583
- ISSN
- 1521-0081
- PMID
- 36779343; PMC9553105
- Organisation Unit
- School of Health; University of the Sunshine Coast, Queensland; Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy
- Language
- English
- Record Identifier
- 99677497802621
- Output Type
- Journal article
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