Carbajales Carlos, Azuaje Jhonny, Oliveira Ana, Loza María I, Brea José, Cadavid María I, Masaguer Christian F, García-Mera Xerardo, Gutiérrez-de-Terán Hugo, Sotelo Eddy
Department of Cell and Molecular Biology, Uppsala University , Uppsala SE-75124, Sweden.
Drug Screening Platform/Biofarma Research Group, Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela , 15782 Santiago de Compostela, Spain.
J Med Chem. 2017 Apr 27;60(8):3372-3382. doi: 10.1021/acs.jmedchem.7b00138. Epub 2017 Apr 11.
A novel family of structurally simple, potent, and selective nonxanthine AAR ligands was identified, and its antagonistic behavior confirmed through functional experiments. The reported alkyl 2-cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahy-dropyrimidine-5-carboxylates (16) were designed by bioisosteric replacement of the carbonyl group at position 2 in a series of 3,4-dihydropyrimidin-2-ones. The scaffold (16) documented herein contains a chiral center at the heterocycle. Accordingly, the most attractive ligand of the series [(±)16b, K = 24.3 nM] was resolved into its two enantiomers by chiral HPLC, and the absolute configuration was established by circular dichroism. The biological evaluation of both enantiomers demonstrated enantiospecific recognition at AAR, with the (S)-16b enantiomer retaining all the affinity (K = 15.1 nM), as predicted earlier by molecular modeling. This constitutes the first example of enantiospecific recognition at the A adenosine receptor and opens new possibilities in ligand design for this receptor.
鉴定出了一类结构简单、高效且具有选择性的新型非黄嘌呤AAR配体，并通过功能实验证实了其拮抗行为。报道的烷基2-氰基亚氨基-4-取代-6-甲基-1,2,3,4-四氢嘧啶-5-羧酸盐（16）是通过对一系列3,4-二氢嘧啶-2-酮中2位羰基进行生物电子等排体取代而设计的。本文记录的支架（16）在杂环处含有一个手性中心。因此，该系列中最具吸引力的配体[（±）16b，K = 24.3 nM]通过手性高效液相色谱法拆分为其两种对映体，并通过圆二色性确定了绝对构型。两种对映体的生物学评价表明在AAR处存在对映体特异性识别，（S）-16b对映体保留了所有亲和力（K = 15.1 nM），正如之前分子建模所预测的那样。这是A腺苷受体对映体特异性识别的首个实例，并为该受体的配体设计开辟了新的可能性。
