Wolfson Laboratory of Medicinal Chemistry, University of Bath, Dept. of Pharmacy and Pharmacology, Claverton Down, Bath, BA2 7AY, UK.
Medicinal Chemistry & Drug Discovery, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
Sci Rep. 2018 Nov 13;8(1):16775. doi: 10.1038/s41598-018-34917-3.
Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca-releasing second messenger known to date, but the precise NAADP/Ca signalling mechanisms are still controversial. We report the synthesis of small-molecule inhibitors of NAADP-induced Ca release based upon the nicotinic acid motif. Alkylation of nicotinic acid with a series of bromoacetamides generated a diverse compound library. However, many members were only weakly active or had poor physicochemical properties. Structural optimisation produced the best inhibitors that interact specifically with the NAADP/Ca release mechanism, having no effect on Ca mobilized by the other well-known second messengers D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P] or cyclic adenosine 5'-diphospho-ribose (cADPR). Lead compound (2) was an efficient antagonist of NAADP-evoked Ca release in vitro in intact T lymphocytes and ameliorated clinical disease in vivo in a rat experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Compound (3) (also known as BZ194) was synthesized as its bromide salt, confirmed by crystallography, and was more membrane permeant than 2. The corresponding zwitterion (3a), was also prepared and studied by crystallography, but 3 had more desirable physicochemical properties. 3 Is potent in vitro and in vivo and has found widespread use as a tool to modulate NAADP effects in autoimmunity and cardiovascular applications. Taken together, data suggest that the NAADP/Ca signalling mechanism may serve as a potential target for T cell- or cardiomyocyte-related diseases such as multiple sclerosis or arrhythmia. Further modification of these lead compounds may potentially result in drug candidates of clinical use.
烟酰胺腺嘌呤二核苷酸磷酸（NAADP）是目前已知的最有效的钙离子释放第二信使，但确切的 NAADP/Ca 信号机制仍存在争议。我们报告了基于烟酸基序的 NAADP 诱导钙释放的小分子抑制剂的合成。烟酸与一系列溴乙酰胺的烷基化生成了一个多样化的化合物文库。然而，许多成员只有微弱的活性或较差的物理化学性质。结构优化产生了与 NAADP/Ca 释放机制特异性相互作用的最佳抑制剂，对其他已知的第二信使 D-肌醇 1,4,5-三磷酸[Ins(1,4,5)P]或环腺苷酸 5'-二磷酸核糖（cADPR）所动员的钙没有影响。先导化合物（2）是体外完整 T 淋巴细胞中 NAADP 诱发钙释放的有效拮抗剂，并在多发性硬化症的大鼠实验性自身免疫性脑脊髓炎（EAE）模型中体内改善了临床疾病。化合物（3）（也称为 BZ194）作为其溴化物盐合成，通过晶体学证实，并比 2 更具膜通透性。相应的两性离子（3a）也被制备并通过晶体学研究，但 3 具有更好的物理化学性质。3 在体外和体内都很有效，并且已广泛用于调节自身免疫和心血管应用中 NAADP 效应的工具。总之，数据表明，NAADP/Ca 信号机制可能成为与 T 细胞或心肌细胞相关的疾病（如多发性硬化症或心律失常）的潜在靶点。这些先导化合物的进一步修饰可能会产生有临床应用潜力的候选药物。
