Novel Functionalized Amino Acids as Inhibitors of GABA Transporters with Analgesic Activity.

Abstract

Neuropathic pain resistance to pharmacotherapy has encouraged researchers to develop effective therapies for its treatment. γ-Aminobutyric acid (GABA) transporters 1 and 4 (mGAT1 and mGAT4) have been increasingly recognized as promising drug targets for neuropathic pain (NP) associated with imbalances in inhibitory neurotransmission. In this context, we designed and synthesized new functionalized amino acids as inhibitors of GABA uptake and assessed their activities toward all four mouse GAT subtypes (mGAT1-4). According to the obtained results, compounds 2RS,4RS-39c (pIC50 (mGAT4) = 5.36), 50a (pIC50 (mGAT2) = 5.43), and 56a (with moderate subtype selectivity that favored mGAT4, pIC50 (mGAT4) = 5.04) were of particular interest and were therefore evaluated for their cytotoxic and hepatotoxic effects. In a set of in vivo experiments, both compounds 50a and 56a showed antinociceptive properties in three rodent models of NP, namely, chemotherapy-induced neuropathic pain models (the oxaliplatin model and the paclitaxel model) and the diabetic neuropathic pain model induced by streptozotocin; however compound 56a demonstrated predominant activity. Since impaired motor coordination is also observed in neuropathic pain conditions, we have pointed out that none of the test compounds induced motor deficits in the rotarod test.

• Authors: Beata Gryzło, Paula Zaręba, Katarzyna Malawska, Gabriela Mazur, Anna Rapacz, Kamil Ła Tka, Georg C Höfner, Gniewomir Latacz, Marek Bajda, Kinga Sałat, Klaus T Wanner, Barbara Malawska, Katarzyna Kulig
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 12 Issue 16 Pg. 3073-3100 (08 18 2021) ISSN: 1948-7193 [Electronic] United States
• PMID: 34347423 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acids
• Analgesics
• GABA Plasma Membrane Transport Proteins
• gamma-Aminobutyric Acid

Topics

• Amino Acids
• Analgesics (pharmacology)
• Animals
• GABA Plasma Membrane Transport Proteins
• Mice
• Neuralgia (drug therapy)
• gamma-Aminobutyric Acid