ANSTO Life Sciences Division, ANSTO, Locked Bag 2001, Kirrawee DC, NSW 2232, Australia.
Org Biomol Chem. 2014 Feb 7;12(5):783-94. doi: 10.1039/c3ob42254b. Epub 2013 Dec 5.
5-Bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxybenzamide 1 is a potent and selective σ2 receptor ligand suitable for further development. A series of new analogues, incorporating a variety of isoquinoline and carboxylic acid moieties, linked together with either a linear or cyclic amine spacer have been synthesised and assessed for their σ1/σ2 binding affinity and selectivity. Compounds with a rigid piperidine spacer gave Ki values for the σ2 receptor between 8.7-845 nM. Changing the configuration of the methoxy groups on the isoquinoline moiety resulted in molecules with σ2Ki values of 4.4-133 nM whereas varying the length and flexibility of the carbon spaces gave σ2Ki values 0.88-15.0 nM, some of the most active, selective σ2 ligands to date. Thus, the flexibility and length of the carbon linker and the carboxylic acid moiety are confirmed to be key to the exceptional binding affinity and selectivity for this active series. Additionally, the incorporation of a halogen on selected carboxylic acid moieties provided a convenient strategy for the introduction of a radiohalogen for applications in pharmacological and imaging studies.
5-溴-N-[4-(6,7-二甲氧基-3,4-二氢-1H-异喹啉-2-基)-丁基)]-2,3-二甲氧基苯甲酰胺 1 是一种强效且选择性的 σ2 受体配体，适合进一步开发。我们合成了一系列新的类似物，将各种异喹啉和羧酸部分连接在一起，分别使用线性或环状胺间隔物，并评估了它们对 σ1/σ2 的结合亲和力和选择性。具有刚性哌啶间隔物的化合物对 σ2 受体的 Ki 值在 8.7-845 nM 之间。改变异喹啉部分上甲氧基的构象，得到 σ2Ki 值为 4.4-133 nM 的分子，而改变碳间隔的长度和灵活性，得到 σ2Ki 值为 0.88-15.0 nM 的分子，其中一些是迄今为止最活跃、选择性最高的 σ2 配体。因此，碳连接体和羧酸部分的灵活性和长度被确认为该活性系列具有优异的结合亲和力和选择性的关键。此外，在选定的羧酸部分上引入卤素提供了一种方便的策略，可用于引入放射性卤素，以应用于药理学和成像研究。
