Identification of N-acyl amino acids that are positive allosteric modulators of glycine receptors.

Gallagher, CI; Sheipouri, D; Shimmon, S; Rawling, T; Vandenberg, RJ

Identification of N-acyl amino acids that are positive allosteric modulators of glycine receptors.

Gallagher, CI Sheipouri, D Shimmon, S Rawling, T

Vandenberg, RJ

Permalink

Publisher:: PERGAMON-ELSEVIER SCIENCE LTD
Publication Type:: Journal Article
Citation:: Biochemical pharmacology, 2020, 180
Issue Date:: 2020-10

Closed Access

	Filename	Description	Size
	1-s2.0-S0006295220303531-main.pdf	Published version	3.5 MB	Adobe PDF	View/Open

Copyright Clearance Process

Recently Added
In Progress
Closed Access

This item is closed access and not available.

Full metadata record

Field	Value	Language
dc.contributor.author	Gallagher, CI
dc.contributor.author	Sheipouri, D
dc.contributor.author	Shimmon, S
dc.contributor.author	Rawling, T https://orcid.org/0000-0002-6624-6586
dc.contributor.author	Vandenberg, RJ
dc.date.accessioned	2020-12-16T00:54:44Z
dc.date.available	2020-06-18
dc.date.available	2020-12-16T00:54:44Z
dc.date.issued	2020-10
dc.identifier.citation	Biochemical pharmacology, 2020, 180
dc.identifier.issn	0006-2952
dc.identifier.issn	1873-2968
dc.identifier.uri	http://hdl.handle.net/10453/144737
dc.description.abstract	Glycine receptors (GlyRs) mediate inhibitory neurotransmission within the spinal cord and play a crucial role in nociceptive signalling. This makes them primary targets for the development of novel chronic pain therapies. Endogenous lipids have previously been shown to modulate glycine receptors and produce analgesia in pain models, however little is known about what chemical features mediate these effects. In this study, we characterised lipid modulation of GlyRs by screening a library of N-acyl amino acids across all receptor subtypes and determined chemical features crucial for their activity. Acyl-glycine's with a C18 carbon tail were found to produce the greatest potentiation, and require a cis double bond within the central region of the carbon tail (ω6 - ω9) to be active. At 1 µM, C18 ω6,9 glycine potentiated glycine induced currents in α3 and α3β receptors by over 50%, and α1, α2, α1β and α2β receptors by over 100%. C18 ω9 glycine (N-oleoyl glycine) significantly enhance glycine induced peak currents and cause a dose-dependent shift in the glycine concentration response. In the presence of 3 µM C18 ω9 glycine, the EC5o of glycine at the α1 receptor was reduced from 17 µM to 10 µM. This study has identified several acyl-amino acids which are positive allosteric modulators of GlyRs and make promising lead compounds for the development of novel chronic pain therapies.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	PERGAMON-ELSEVIER SCIENCE LTD
dc.relation	http://purl.org/au-research/grants/nhmrc/GNT1082570
dc.relation	http://purl.org/au-research/grants/nhmrc/APP1144429
dc.relation	http://purl.org/au-research/grants/nhmrc/GNT1144429
dc.relation.ispartof	Biochemical pharmacology
dc.relation.isbasedon	10.1016/j.bcp.2020.114117
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	0601 Biochemistry and Cell Biology, 1115 Pharmacology and Pharmaceutical Sciences
dc.subject.classification	Pharmacology & Pharmacy
dc.title	Identification of N-acyl amino acids that are positive allosteric modulators of glycine receptors.
dc.type	Journal Article
utslib.citation.volume	180
utslib.location.activity	England
utslib.for	0601 Biochemistry and Cell Biology
utslib.for	1115 Pharmacology and Pharmaceutical Sciences
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
pubs.organisational-group	/University of Technology Sydney
utslib.copyright.status	closed_access	*
pubs.consider-herdc	false
dc.date.updated	2020-12-16T00:54:32Z
pubs.publication-status	Published
pubs.volume	180

Abstract:

Glycine receptors (GlyRs) mediate inhibitory neurotransmission within the spinal cord and play a crucial role in nociceptive signalling. This makes them primary targets for the development of novel chronic pain therapies. Endogenous lipids have previously been shown to modulate glycine receptors and produce analgesia in pain models, however little is known about what chemical features mediate these effects. In this study, we characterised lipid modulation of GlyRs by screening a library of N-acyl amino acids across all receptor subtypes and determined chemical features crucial for their activity. Acyl-glycine's with a C18 carbon tail were found to produce the greatest potentiation, and require a cis double bond within the central region of the carbon tail (ω6 - ω9) to be active. At 1 µM, C18 ω6,9 glycine potentiated glycine induced currents in α3 and α3β receptors by over 50%, and α1, α2, α1β and α2β receptors by over 100%. C18 ω9 glycine (N-oleoyl glycine) significantly enhance glycine induced peak currents and cause a dose-dependent shift in the glycine concentration response. In the presence of 3 µM C18 ω9 glycine, the EC5o of glycine at the α1 receptor was reduced from 17 µM to 10 µM. This study has identified several acyl-amino acids which are positive allosteric modulators of GlyRs and make promising lead compounds for the development of novel chronic pain therapies.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/144737