Department of Anaesthesiology and Intensive Care, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany.
Department of Anaesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany.
Biomolecules. 2021 Mar 25;11(4):493. doi: 10.3390/biom11040493.
Treating neuropathic pain remains challenging, and therefore new pharmacological strategies are urgently required. Here, the enhancement of glycinergic neurotransmission by either facilitating glycine receptors (GlyR) or inhibiting glycine transporter (GlyT) function to increase extracellular glycine concentration appears promising. Propacetamol is a ,-diethylester of acetaminophen, a non-opioid analgesic used to treat mild pain conditions. In vivo, it is hydrolysed into ,-diethylglycine (DEG) and acetaminophen. DEG has structural similarities to known alternative GlyT1 substrates. In this study, we analyzed possible effects of propacetamol, or its metabolite ,-diethylglycine (DEG), on GlyRs or GlyTs function by using a two-electrode voltage clamp approach in oocytes. Our data demonstrate that, although propacetamol or acetaminophen had no effect on the function of the analysed glycine-responsive proteins, the propacetamol metabolite DEG acted as a low-affine substrate for both GlyT1 (EC50 > 7.6 mM) and GlyT2 (EC50 > 5.2 mM). It also acted as a mild positive allosteric modulator of GlyRα1 function at intermediate concentrations. Taken together, our data show that DEG influences both glycine transporter and receptor function, and therefore could facilitate glycinergic neurotransmission in a multimodal manner.
治疗神经病理性疼痛仍然具有挑战性，因此迫切需要新的药理学策略。在这里，通过促进甘氨酸受体（GlyR）或抑制甘氨酸转运体（GlyT）的功能来增加细胞外甘氨酸浓度，从而增强甘氨酸能神经传递，这似乎很有希望。丙戊酰氨酚是一种对乙酰氨基酚的，-二乙酯，一种非阿片类镇痛药，用于治疗轻度疼痛。在体内，它被水解成，-二乙基甘氨酸（DEG）和对乙酰氨基酚。DEG 与已知的替代 GlyT1 底物具有结构相似性。在这项研究中，我们通过在卵母细胞中使用双电极电压钳方法分析了丙戊酰氨酚或其代谢物，-二乙基甘氨酸（DEG）对 GlyRs 或 GlyTs 功能的可能影响。我们的数据表明，尽管丙戊酰氨酚或对乙酰氨基酚对分析的甘氨酸反应蛋白的功能没有影响，但丙戊酰氨酚代谢物 DEG 作为 GlyT1（EC50>7.6mM）和 GlyT2（EC50>5.2mM）的低亲和力底物起作用。它还在中间浓度下作为 GlyRα1 功能的轻度正变构调节剂起作用。总之，我们的数据表明 DEG 影响甘氨酸转运体和受体的功能，因此可以以多模式方式促进甘氨酸能神经传递。
