Abstract：
An increasing number of drugs introduced to the market and numerous repositories of compounds with confirmed activity have posed the need to revalidate the state-of-the-art rules that determine the ranges of properties the compounds should possess to become future drugs. In this study, we designed a series of two chemotypes of aryl-piperazine hydantoin ligands of 5-HT7R, an attractive target in search for innovative CNS drugs, with higher molecular weight (close to or over 500). Consequently, 14 new compounds were synthesised and screened for their receptor activity accompanied by extensive docking studies to evaluate the observed structure-activity/properties relationships. The ADMET characterisation in terms of the biological membrane permeability, metabolic stability, hepatotoxicity, cardiotoxicity, and protein plasma binding of the obtained compounds was carried out in vitro. The outcome of these studies constituted the basis for the comprehensive challenge of computational tools for ADMET properties prediction. All the compounds possessed high affinity to the 5-HT7R (Ki below 250 nM for all analysed structures) with good selectivity over 5-HT6R and varying affinity towards 5-HT2AR, 5-HT1AR and D2R. For the best compounds of this study, the expression profile of genes associated with neurodegeneration, anti-oxidant response and anti-inflammatory function was determined, and the survival of the cells (SH-SY5Y as an in vitro model of Alzheimer\'s disease) was evaluated. One 5-HT7R agent (32) was characterised by a very promising ADMET profile, i.e. good membrane permeability, low hepatotoxicity and cardiotoxicity, and high metabolic stability with the simultaneous high rate of plasma protein binding and high selectivity over other GPCRs considered, together with satisfying gene expression profile modulations and neural cell survival. Such encouraging properties make it a good candidate for further testing and optimisation as a potential agent in the treatment of CNS-related disorders.
摘要：
引入市场的越来越多的药物和具有证实的活性的化合物的众多存储库已经提出了重新验证确定化合物成为未来药物应具有的性质范围的现有技术规则的需要。在这项研究中,我们设计了一系列两种化学型的芳基哌嗪海因配体5-HT7R，寻找创新中枢神经系统药物的一个有吸引力的目标，具有较高的分子量（接近或超过500）。因此,合成了14种新化合物，并筛选了其受体活性，并进行了广泛的对接研究，以评估所观察到的结构-活性/性质关系。ADMET在生物膜通透性方面的表征，代谢稳定性，肝毒性，心脏毒性,在体外进行所得化合物的蛋白质血浆结合。这些研究的结果构成了ADMET属性预测计算工具全面挑战的基础。所有化合物对5-HT7R具有高亲和力（所有分析结构的Ki低于250nM），对5-HT6R具有良好的选择性，对5-HT2AR具有不同的亲和力，5-HT1AR和D2R。对于这项研究中最好的化合物，与神经变性相关的基因的表达谱，确定抗氧化反应和抗炎功能，和细胞的存活(SH-SY5Y作为阿尔茨海默病的体外模型)进行评估。一种5-HT7R试剂（32）的特征是非常有前途的ADMET概况，即良好的膜渗透性，低肝毒性和心脏毒性，和高代谢稳定性，同时具有较高的血浆蛋白结合率和相对于其他GPCRs的高选择性，以及令人满意的基因表达谱调制和神经细胞存活。这种令人鼓舞的特性使其成为进一步测试和优化的良好候选药物，可作为治疗CNS相关疾病的潜在药物。
