Development of an N-Acyl Amino Acid That Selectively Inhibits the Glycine Transporter 2 to Produce Analgesia in a Rat Model of Chronic Pain

Mostyn, SN; Rawling, T; Mohammadi, S; Shimmon, S; Frangos, ZJ; Sarker, S; Yousuf, A; Vetter, I; Ryan, RM; Christie, MJ; Vandenberg, RJ

Development of an N-Acyl Amino Acid That Selectively Inhibits the Glycine Transporter 2 to Produce Analgesia in a Rat Model of Chronic Pain

Mostyn, SN Rawling, T

Mohammadi, S Shimmon, S Frangos, ZJ Sarker, S Yousuf, A Vetter, I Ryan, RM Christie, MJ Vandenberg, RJ

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Publication Type:: Journal Article
Citation:: Journal of Medicinal Chemistry, 2019, 62 (5), pp. 2466 - 2484
Issue Date:: 2019-03-14

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Field	Value	Language
dc.contributor.author	Mostyn, SN	en_US
dc.contributor.author	Rawling, T https://orcid.org/0000-0002-6624-6586	en_US
dc.contributor.author	Mohammadi, S	en_US
dc.contributor.author	Shimmon, S	en_US
dc.contributor.author	Frangos, ZJ	en_US
dc.contributor.author	Sarker, S	en_US
dc.contributor.author	Yousuf, A	en_US
dc.contributor.author	Vetter, I	en_US
dc.contributor.author	Ryan, RM	en_US
dc.contributor.author	Christie, MJ	en_US
dc.contributor.author	Vandenberg, RJ	en_US
dc.date.issued	2019-03-14	en_US
dc.identifier.citation	Journal of Medicinal Chemistry, 2019, 62 (5), pp. 2466 - 2484	en_US
dc.identifier.issn	0022-2623	en_US
dc.identifier.uri	http://hdl.handle.net/10453/135093
dc.description.abstract	© 2019 American Chemical Society. Inhibitors that target the glycine transporter 2, GlyT2, show promise as analgesics, but may be limited by their toxicity through complete or irreversible binding. Acyl-glycine inhibitors, however, are selective for GlyT2 and have been shown to provide analgesia in animal models of pain with minimal side effects, but are comparatively weak GlyT2 inhibitors. Here, we modify the simple acyl-glycine by synthesizing lipid analogues with a range of amino acid head groups in both l- and d-configurations, to produce nanomolar affinity, selective GlyT2 inhibitors. The potent inhibitor oleoyl-d-lysine (33) is also resistant to degradation in both human and rat plasma and liver microsomes, and is rapidly absorbed following an intraperitoneal injection to rats and readily crosses the blood-brain barrier. We demonstrate that 33 provides greater analgesia at lower doses, and does not possess the severe side effects of the very slowly reversible GlyT2 inhibitor, ORG25543 (2).	en_US
dc.relation.ispartof	Journal of Medicinal Chemistry	en_US
dc.relation.isbasedon	10.1021/acs.jmedchem.8b01775	en_US
dc.subject.classification	Medicinal & Biomolecular Chemistry	en_US
dc.title	Development of an N-Acyl Amino Acid That Selectively Inhibits the Glycine Transporter 2 to Produce Analgesia in a Rat Model of Chronic Pain	en_US
dc.type	Journal Article
utslib.citation.volume	5	en_US
utslib.citation.volume	62	en_US
utslib.for	0304 Medicinal and Biomolecular Chemistry	en_US
utslib.for	0305 Organic Chemistry	en_US
utslib.for	1115 Pharmacology and Pharmaceutical Sciences	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	closed_access
pubs.issue	5	en_US
pubs.publication-status	Published	en_US
pubs.volume	62	en_US

Abstract:

© 2019 American Chemical Society. Inhibitors that target the glycine transporter 2, GlyT2, show promise as analgesics, but may be limited by their toxicity through complete or irreversible binding. Acyl-glycine inhibitors, however, are selective for GlyT2 and have been shown to provide analgesia in animal models of pain with minimal side effects, but are comparatively weak GlyT2 inhibitors. Here, we modify the simple acyl-glycine by synthesizing lipid analogues with a range of amino acid head groups in both l- and d-configurations, to produce nanomolar affinity, selective GlyT2 inhibitors. The potent inhibitor oleoyl-d-lysine (33) is also resistant to degradation in both human and rat plasma and liver microsomes, and is rapidly absorbed following an intraperitoneal injection to rats and readily crosses the blood-brain barrier. We demonstrate that 33 provides greater analgesia at lower doses, and does not possess the severe side effects of the very slowly reversible GlyT2 inhibitor, ORG25543 (2).

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

http://hdl.handle.net/10453/135093