Novel Phenylene Lipids That Are Positive Allosteric Modulators of Glycine Receptors and Inhibitors of Glycine Transporter 2.

Gallagher, CI; Frangos, ZJ; Sheipouri, D; Shimmon, S; Duman, M-N; Jayakumar, S; Cioffi, CL; Rawling, T; Vandenberg, RJ

Novel Phenylene Lipids That Are Positive Allosteric Modulators of Glycine Receptors and Inhibitors of Glycine Transporter 2.

Gallagher, CI Frangos, ZJ Sheipouri, D Shimmon, S Duman, M-N Jayakumar, S Cioffi, CL Rawling, T

Vandenberg, RJ

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Publisher:: AMER CHEMICAL SOC
Publication Type:: Journal Article
Citation:: ACS Chem Neurosci, 2023, 14, (15), pp. 2634-2647
Issue Date:: 2023-08-02

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Field	Value	Language
dc.contributor.author	Gallagher, CI
dc.contributor.author	Frangos, ZJ
dc.contributor.author	Sheipouri, D
dc.contributor.author	Shimmon, S
dc.contributor.author	Duman, M-N
dc.contributor.author	Jayakumar, S
dc.contributor.author	Cioffi, CL
dc.contributor.author	Rawling, T https://orcid.org/0000-0002-6624-6586
dc.contributor.author	Vandenberg, RJ
dc.date.accessioned	2024-02-06T03:18:30Z
dc.date.available	2024-02-06T03:18:30Z
dc.date.issued	2023-08-02
dc.identifier.citation	ACS Chem Neurosci, 2023, 14, (15), pp. 2634-2647
dc.identifier.issn	1948-7193
dc.identifier.issn	1948-7193
dc.identifier.uri	http://hdl.handle.net/10453/175355
dc.description.abstract	Chronic pain is a complex condition that remains resistant to current therapeutics. We previously synthesized a series of N-acyl amino acids (NAAAs) that inhibit the glycine transporter, GlyT2, some of which are also positive allosteric modulators of glycine receptors (GlyRs). In this study, we have synthesized a library of NAAAs that contain a phenylene ring within the acyl tail with the objective of improving efficacy at both GlyT2 and GlyRs and also identifying compounds that are efficacious as dual-acting modulators to enhance glycine neurotransmission. The most efficacious positive allosteric modulator of GlyRs was 2-[8-(2-octylphenyl)octanoylamino]acetic acid (8-8 OPGly) which potentiates the EC5 for glycine activation of GlyRα1 by 1500% with an EC50 of 664 nM. Phenylene-containing NAAAs with a lysine headgroup were the most potent inhibitors of GlyT2 with (2S)-6-amino-2-[8-(3-octylphenyl)octanoylamino]hexanoic acid (8-8 MPLys) inhibiting GlyT2 with an IC50 of 32 nM. The optimal modulator across both proteins was (2S)-6-amino-2-[8-(2-octylphenyl)octanoylamino]hexanoic acid (8-8 OPLys), which inhibits GlyT2 with an IC50 of 192 nM and potentiates GlyRs by up to 335% at 1 μM. When tested in a dual GlyT2/GlyRα1 expression system, 8-8 OPLys caused the greatest reductions in the EC50 for glycine. This suggests that the synergistic effects of a dual-acting modulator cause greater enhancements in glycinergic activity compared to single-target modulators and may provide an alternate approach to the development of new non-opioid analgesics for the treatment of chronic pain.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	AMER CHEMICAL SOC
dc.relation.ispartof	ACS Chem Neurosci
dc.relation.isbasedon	10.1021/acschemneuro.3c00167
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	0304 Medicinal and Biomolecular Chemistry
dc.subject.classification	3101 Biochemistry and cell biology
dc.subject.classification	3401 Analytical chemistry
dc.subject.classification	3404 Medicinal and biomolecular chemistry
dc.subject.mesh	Humans
dc.subject.mesh	Glycine Plasma Membrane Transport Proteins
dc.subject.mesh	Receptors, Glycine
dc.subject.mesh	Chronic Pain
dc.subject.mesh	Caproates
dc.subject.mesh	Glycine
dc.subject.mesh	Amino Acids
dc.subject.mesh	Humans
dc.subject.mesh	Caproates
dc.subject.mesh	Amino Acids
dc.subject.mesh	Glycine
dc.subject.mesh	Receptors, Glycine
dc.subject.mesh	Glycine Plasma Membrane Transport Proteins
dc.subject.mesh	Chronic Pain
dc.subject.mesh	Humans
dc.subject.mesh	Glycine Plasma Membrane Transport Proteins
dc.subject.mesh	Receptors, Glycine
dc.subject.mesh	Chronic Pain
dc.subject.mesh	Caproates
dc.subject.mesh	Glycine
dc.subject.mesh	Amino Acids
dc.title	Novel Phenylene Lipids That Are Positive Allosteric Modulators of Glycine Receptors and Inhibitors of Glycine Transporter 2.
dc.type	Journal Article
utslib.citation.volume	14
utslib.location.activity	United States
utslib.for	0304 Medicinal and Biomolecular Chemistry
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	*
dc.date.updated	2024-02-06T03:18:28Z
pubs.issue	15
pubs.publication-status	Published
pubs.volume	14
utslib.citation.issue	15

Abstract:

Chronic pain is a complex condition that remains resistant to current therapeutics. We previously synthesized a series of N-acyl amino acids (NAAAs) that inhibit the glycine transporter, GlyT2, some of which are also positive allosteric modulators of glycine receptors (GlyRs). In this study, we have synthesized a library of NAAAs that contain a phenylene ring within the acyl tail with the objective of improving efficacy at both GlyT2 and GlyRs and also identifying compounds that are efficacious as dual-acting modulators to enhance glycine neurotransmission. The most efficacious positive allosteric modulator of GlyRs was 2-[8-(2-octylphenyl)octanoylamino]acetic acid (8-8 OPGly) which potentiates the EC5 for glycine activation of GlyRα1 by 1500% with an EC50 of 664 nM. Phenylene-containing NAAAs with a lysine headgroup were the most potent inhibitors of GlyT2 with (2S)-6-amino-2-[8-(3-octylphenyl)octanoylamino]hexanoic acid (8-8 MPLys) inhibiting GlyT2 with an IC50 of 32 nM. The optimal modulator across both proteins was (2S)-6-amino-2-[8-(2-octylphenyl)octanoylamino]hexanoic acid (8-8 OPLys), which inhibits GlyT2 with an IC50 of 192 nM and potentiates GlyRs by up to 335% at 1 μM. When tested in a dual GlyT2/GlyRα1 expression system, 8-8 OPLys caused the greatest reductions in the EC50 for glycine. This suggests that the synergistic effects of a dual-acting modulator cause greater enhancements in glycinergic activity compared to single-target modulators and may provide an alternate approach to the development of new non-opioid analgesics for the treatment of chronic pain.

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http://hdl.handle.net/10453/175355