التفاصيل البيبلوغرافية
| العنوان: |
Novel Phenylene Lipids That Are Positive Allosteric Modulators of Glycine Receptors and Inhibitors of Glycine Transporter 2. |
| المؤلفون: |
Gallagher, CI, Frangos, ZJ, Sheipouri, D, Shimmon, S, Duman, M-N, Jayakumar, S, Cioffi, CL, Rawling, T, Vandenberg, RJ |
| بيانات النشر: |
AMER CHEMICAL SOC |
| سنة النشر: |
2024 |
| المجموعة: |
University of Technology Sydney: OPUS - Open Publications of UTS Scholars |
| مصطلحات موضوعية: |
0304 Medicinal and Biomolecular Chemistry, 3101 Biochemistry and cell biology, 3401 Analytical chemistry, 3404 Medicinal and biomolecular chemistry, Humans, Glycine Plasma Membrane Transport Proteins, Receptors, Glycine, Chronic Pain, Caproates, Amino Acids |
| الوصف: |
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. |
| نوع الوثيقة: |
article in journal/newspaper |
| وصف الملف: |
Print-Electronic; application/pdf |
| اللغة: |
English |
| تدمد: |
1948-7193 |
| العلاقة: |
ACS Chem Neurosci; ACS Chem Neurosci, 2023, 14, (15), pp. 2634-2647; http://hdl.handle.net/10453/175355Test |
| الإتاحة: |
http://hdl.handle.net/10453/175355Test |
| حقوق: |
info:eu-repo/semantics/closedAccess |
| رقم الانضمام: |
edsbas.A7C811B |
| قاعدة البيانات: |
BASE |
