School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.
Irish Centre of High-End Computing, Grand Canal Quay, Dublin 2, Ireland.
Eur J Med Chem. 2017 Sep 29;138:38-50. doi: 10.1016/j.ejmech.2017.06.008. Epub 2017 Jun 6.
Searching for improved antagonists of α-adrenoceptors, a thorough theoretical study comparing the aromaticity of phenyl-, pyridinyl-, thiophenyl- and thiazolylguanidinium derivatives has been carried out [at M06-2X/6-311++G(p,d) computational level] confirming that thiophene and thiazole will be good 'ring equivalents' to benzene in these guanidinium systems. Based on these results, a small but chemically diverse library of guanidine derivatives (15 thiophenes and 2 thiazoles) were synthesised to explore the effect that the bioisosteric change has on affinity and activity at α-adrenoceptors in comparison with our previously studied phenyl derivatives. All compounds were tested for their α-adrenoceptor affinity and unsubstituted guanidinothiophenes displayed the strongest affinities in the same range as the phenyl analogues. In the case of cycloakyl systems, thiophenes with 6-membered rings showed the largest affinities, while for the thiazoles the 5-membered analogue presented the strongest affinity. From all the compounds tested for noradrenergic activity, only one compound exhibited agonistic activity, while two compounds showed very promising antagonism of α-adrenoceptors.
为了寻找α-肾上腺素受体的改良拮抗剂，我们进行了一项彻底的理论研究，比较了苯基、吡啶基、噻吩基和噻唑基胍衍生物的芳香性[在 M06-2X/6-311++G(p,d)计算水平上]，证实噻吩和噻唑将是这些胍系统中苯的良好“环等价物”。基于这些结果，我们合成了一个小而化学多样性的胍衍生物文库（15 个噻吩和 2 个噻唑），以探索生物等排体变化对与我们之前研究的苯基衍生物相比在α-肾上腺素受体上的亲和力和活性的影响。所有化合物都进行了α-肾上腺素受体亲和力测试，未取代的胍噻吩的亲和力与苯基类似物相同，处于同一范围内。在环状系统的情况下，具有 6 元环的噻吩显示出最大的亲和力，而对于噻唑，5 元类似物具有最强的亲和力。在所测试的所有具有去甲肾上腺素能活性的化合物中，只有一种化合物表现出激动活性，而两种化合物表现出对α-肾上腺素受体非常有希望的拮抗作用。
