Tamborini Lucia, Cullia Gregorio, Nielsen Birgitte, De Micheli Carlo, Conti Paola, Pinto Andrea
Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133 Milan, Italy.
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen OE, Denmark.
Bioorg Med Chem. 2016 Nov 15;24(22):5741-5747. doi: 10.1016/j.bmc.2016.09.029. Epub 2016 Sep 12.
Homologation of glutamic acid chain together with conformational constraint is a commonly used strategy to achieve selectivity towards different types of glutamate receptors. In the present work, starting from two potent and selective unnatural amino acids previously developed by us, we investigated the effects on the activity/selectivity profile produced by a further increase in the distance between the amino acidic moiety and the distal carboxylate group. Interestingly, the insertion of an aromatic ring as a spacer produced a low micromolar affinity NMDA ligand that might represent a lead for the development of a new class of NMDA antagonists.
将谷氨酸链进行同源化并结合构象限制是实现对不同类型谷氨酸受体选择性的常用策略。在本研究中，我们从之前开发的两种强效且选择性的非天然氨基酸出发，研究了氨基酸部分与远端羧酸根基团之间距离进一步增加对活性/选择性特征的影响。有趣的是，插入一个芳香环作为间隔基产生了一种低微摩尔亲和力的NMDA配体，这可能代表了开发新型NMDA拮抗剂的一个先导化合物。
