Glycine Receptor Drug Discovery

Lynch, Joseph W., Zhang, Yan, Talwar, Sahil and Estrada-Mondragon, Argel (2017) Glycine Receptor Drug Discovery. Advances in Pharmacology, 79 225-253. doi:10.1016/bs.apha.2017.01.003

Author Lynch, Joseph W.
Zhang, Yan
Talwar, Sahil
Estrada-Mondragon, Argel
Title Glycine Receptor Drug Discovery
Journal name Advances in Pharmacology   Check publisher's open access policy
ISSN 1557-8925
Publication date 2017-04-01
Sub-type Article (original research)
DOI 10.1016/bs.apha.2017.01.003
Open Access Status Not yet assessed
Volume 79
Start page 225
End page 253
Total pages 29
Place of publication Maryland Heights, MO United States
Publisher Academic Press
Language eng
Subject 3004 Pharmacology
Abstract Postsynaptic glycine receptor (GlyR) chloride channels mediate inhibitory neurotransmission in the spinal cord and brain stem, although presynaptic and extrasynaptic GlyRs are expressed more widely throughout the brain. In humans, GlyRs are assembled as homo- or heteromeric pentamers of α1-3 and β subunits. GlyR malfunctions have been linked to a range of neurological disorders including hyperekplexia, temporal lobe epilepsy, autism, breathing disorders, and chronic inflammatory pain. Although it is possible that GlyRs may eventually be clinically targeted for a variety of neurological disorders, most research to date has focused on developing GlyR-targeted treatments for chronic pain. Inflammatory pain sensitization is caused by inflammatory mediators downregulating the magnitude of α3 GlyR-mediated inhibitory postsynaptic currents in spinal nociceptive neurons. Consistent with this paradigm, it is now well established that the selective enhancement of α3 GlyR current magnitude is effective in alleviating inflammatory pain. In this review, we briefly describe the physiological roles and pharmacological properties of GlyRs. We then outline the methods commonly used to discover new GlyR-active compounds and review recent progress, in our laboratory and elsewhere, in developing GlyR-targeted analgesics. We conclude that the eventual development of an α3 GlyR-targeted analgesic is an eminently feasible goal. However, in selecting or designing new therapeutic leads, we caution against the automatic exclusion of compounds with potentiating effects on α1 GlyRs. Also, as GlyRs are strongly potentiated by Zn at nanomolar concentrations, we also caution against the identification of false positives caused by contaminating Zn in otherwise pure compound samples.
Keyword Alcoholism
Breathing disorders
Motor neuron disease
Temporal lobe epilepsy
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
School of Biomedical Sciences Publications
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