Synthesis and Characterization of Novel Acyl-Glycine Inhibitors of GlyT2

Mostyn, SN; Carland, JE; Shimmon, S; Ryan, RM; Rawling, T; Vandenberg, RJ

Synthesis and Characterization of Novel Acyl-Glycine Inhibitors of GlyT2

Mostyn, SN Carland, JE Shimmon, S Ryan, RM Rawling, T

Vandenberg, RJ

Permalink

Publication Type:: Journal Article
Citation:: ACS Chemical Neuroscience, 2017, 8 (9), pp. 1949 - 1959
Issue Date:: 2017-09-20

Open Access

Copyright Clearance Process

Recently Added
In Progress
Open Access

This item is open access.

Adobe PDF

Download Accepted Manuscript VersionAdobe PDF (781.87 kB)

View on publisher's site

View statistics

Full metadata record

Field	Value	Language
dc.contributor.author	Mostyn, SN	en_US
dc.contributor.author	Carland, JE	en_US
dc.contributor.author	Shimmon, S	en_US
dc.contributor.author	Ryan, RM	en_US
dc.contributor.author	Rawling, T https://orcid.org/0000-0002-6624-6586	en_US
dc.contributor.author	Vandenberg, RJ	en_US
dc.date.available	2020-05-25T19:05:12Z
dc.date.issued	2017-09-20	en_US
dc.identifier.citation	ACS Chemical Neuroscience, 2017, 8 (9), pp. 1949 - 1959	en_US
dc.identifier.uri	http://hdl.handle.net/10453/125181
dc.description.abstract	© 2017 American Chemical Society. It has been demonstrated previously that the endogenous compound N-arachidonyl-glycine inhibits the glycine transporter GlyT2, stimulates glycinergic neurotransmission, and provides analgesia in animal models of neuropathic and inflammatory pain. However, it is a relatively weak inhibitor with an IC50 of 9 μM and is subject to oxidation via cyclooxygenase, limiting its therapeutic value. In this paper we describe the synthesis and testing of a novel series of monounsaturated C18 and C16 acyl-glycine molecules as inhibitors of the glycine transporter GlyT2. We demonstrate that they are up to 28 fold more potent that N-arachidonyl-glycine with no activity at the closely related GlyT1 transporter at concentrations up to 30 μM. This novel class of compounds show considerable promise as a first generation of GlyT2 transport inhibitors.	en_US
dc.relation	http://purl.org/au-research/grants/nhmrc/GNT1082570
dc.relation.ispartof	ACS Chemical Neuroscience	en_US
dc.relation.isbasedon	10.1021/acschemneuro.7b00105	en_US
dc.subject.mesh	Oocytes	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Xenopus laevis	en_US
dc.subject.mesh	Tritium	en_US
dc.subject.mesh	Arachidonic Acids	en_US
dc.subject.mesh	Glycine	en_US
dc.subject.mesh	RNA, Messenger	en_US
dc.subject.mesh	Analgesics	en_US
dc.subject.mesh	Molecular Structure	en_US
dc.subject.mesh	Membrane Potentials	en_US
dc.subject.mesh	Micelles	en_US
dc.subject.mesh	Membrane Transport Modulators	en_US
dc.subject.mesh	Glycine Plasma Membrane Transport Proteins	en_US
dc.title	Synthesis and Characterization of Novel Acyl-Glycine Inhibitors of GlyT2	en_US
dc.type	Journal Article
utslib.citation.volume	9	en_US
utslib.citation.volume	8	en_US
utslib.for	0299 Other Physical Sciences	en_US
utslib.for	0303 Macromolecular and Materials Chemistry	en_US
utslib.for	0304 Medicinal and Biomolecular Chemistry	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
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
utslib.copyright.status	open_access
pubs.issue	9	en_US
pubs.publication-status	Published	en_US
pubs.volume	8	en_US

Abstract:

© 2017 American Chemical Society. It has been demonstrated previously that the endogenous compound N-arachidonyl-glycine inhibits the glycine transporter GlyT2, stimulates glycinergic neurotransmission, and provides analgesia in animal models of neuropathic and inflammatory pain. However, it is a relatively weak inhibitor with an IC50 of 9 μM and is subject to oxidation via cyclooxygenase, limiting its therapeutic value. In this paper we describe the synthesis and testing of a novel series of monounsaturated C18 and C16 acyl-glycine molecules as inhibitors of the glycine transporter GlyT2. We demonstrate that they are up to 28 fold more potent that N-arachidonyl-glycine with no activity at the closely related GlyT1 transporter at concentrations up to 30 μM. This novel class of compounds show considerable promise as a first generation of GlyT2 transport inhibitors.

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

http://hdl.handle.net/10453/125181