Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Catania, Italy.
Bioorg Med Chem. 2011 Sep 1;19(17):5260-76. doi: 10.1016/j.bmc.2011.06.043. Epub 2011 Jun 21.
Three different series of 1H-pyrrolopyrimidine-2,4-dione derivatives were designed and synthesized as ligands for the α(1)-adrenergic receptors (α(1)-ARs). A microwave-assisted protocol was developed in order to improve purity and yields of some final products. The majority of the synthesized compounds, tested in binding assays, displayed α(1)-AR affinities in the nanomolar range. Highest affinity values were found in derivatives 10b and 10c (K(i)=1.4 nM for both) whereas compound 10e was endowed with the best profile in term of α(1)-AR affinity (K(i)=2.71 nM) coupled with high selectivity towards 5-HT(1A) receptors (K(i) >10,000). Molecular docking studies were performed on human α(1)-ARs and human 5-HT(1A) receptors in order to rationalize the observed experimental affinity and selectivity; these computational studies helped to clarify molecular requirements for the design of high-selective α(1)-adrenergic ligands.
设计并合成了三个不同系列的 1H-吡咯并[2,3-d]嘧啶-2,4-二酮衍生物作为α(1)-肾上腺素能受体（α(1)-ARs）的配体。为了提高某些最终产物的纯度和产率，开发了一种微波辅助方案。在结合测定中测试的大多数合成化合物均显示出纳摩尔范围内的α(1)-AR 亲和力。在衍生物 10b 和 10c 中发现了最高的亲和力值（K(i)=1.4 nM），而化合物 10e 在α(1)-AR 亲和力方面具有最佳的特性（K(i)=2.71 nM），同时对 5-HT(1A)受体具有高选择性（K(i)>10,000）。进行了分子对接研究，以研究人类α(1)-ARs 和人类 5-HT(1A)受体，以合理地解释观察到的实验亲和力和选择性；这些计算研究有助于阐明设计高选择性α(1)-肾上腺素能配体的分子要求。
