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Papers of the Week

Papers: 22 Jul 2023 - 28 Jul 2023

Basic Science

In Vitro Studies, Pharmacology/Drug Development

2023 Jul 19

ACS Chem Neurosci


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 MN, Jayakumar S, Cioffi CL, Rawling T, Vandenberg RJ


Chronic pain is a complex condition that remains resistant to current therapeutics. We previously synthesized a series of -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 EC for glycine activation of GlyRα by 1500% with an EC of 664 nM. Phenylene-containing NAAAs with a lysine headgroup were the most potent inhibitors of GlyT2 with (2)-6-amino-2-[8-(3-octylphenyl)octanoylamino]hexanoic acid (8-8 MPLys) inhibiting GlyT2 with an IC of 32 nM. The optimal modulator across both proteins was (2)-6-amino-2-[8-(2-octylphenyl)octanoylamino]hexanoic acid (8-8 OPLys), which inhibits GlyT2 with an IC of 192 nM and potentiates GlyRs by up to 335% at 1 μM. When tested in a dual GlyT2/GlyRα expression system, 8-8 OPLys caused the greatest reductions in the EC 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.