Discipline of Pharmacology, School of Medical Sciences, University of Sydney , Sydney, NSW 2006, Australia.
School of Mathematical and Physical Sciences, Faculty of Science, The University of Technology Sydney , Sydney, NSW 2007, Australia.
ACS Chem Neurosci. 2017 Sep 20;8(9):1949-1959. doi: 10.1021/acschemneuro.7b00105. Epub 2017 Jun 15.
It has been demonstrated previously that the endogenous compound N-arachidonyl-glycine inhibits the glycine transporter GlyT2, stimulates glycinergic neurotransmission, and provides analgesia in animal models of neuropathic and inflammatory pain. However, it is a relatively weak inhibitor with an IC of 9 μM and is subject to oxidation via cyclooxygenase, limiting its therapeutic value. In this paper we describe the synthesis and testing of a novel series of monounsaturated C18 and C16 acyl-glycine molecules as inhibitors of the glycine transporter GlyT2. We demonstrate that they are up to 28 fold more potent that N-arachidonyl-glycine with no activity at the closely related GlyT1 transporter at concentrations up to 30 μM. This novel class of compounds show considerable promise as a first generation of GlyT2 transport inhibitors.
先前已经证实，内源性化合物 N-花生四烯酰基甘氨酸抑制甘氨酸转运体 GlyT2，刺激甘氨酸能神经传递，并在神经病理性和炎性疼痛的动物模型中提供镇痛作用。然而，它是一种相对较弱的抑制剂，IC 为 9 μM，并且通过环加氧酶发生氧化，限制了其治疗价值。在本文中，我们描述了一系列新型单不饱和 C18 和 C16 酰基甘氨酸分子的合成和测试，作为甘氨酸转运体 GlyT2 的抑制剂。我们证明，它们的效力比 N-花生四烯酰基甘氨酸高 28 倍，在高达 30 μM 的浓度下对密切相关的 GlyT1 转运体没有活性。这类新型化合物显示出作为第一代 GlyT2 转运抑制剂的巨大潜力。
