吡唑并[1,5-α]吡啶类化合物的合成及其体外受体结合分析

以吡唑并[1,5-α]吡啶-3-甲醛和N-甲酰基哌嗪为原料，经过还原胺化、水解和N-烷基化反应，合成了3-(4-苄基哌嗪-1-基甲基)吡唑并[1,5-α]吡啶、3-[4-(4-氯苄基)哌嗪-1-基甲基]吡唑并[1,5-α]吡啶和3-[4-(4-甲氧基苄基)哌嗪-1-基甲基]吡唑并[1,5-α]吡啶，通过1H NMR、ESI MS等技术手段对中间体及3个目标化合物进行了表征，并通过体外受体结合实验，测定3个目标化合物对多巴胺D4.2受体的亲和常数(Ki)分别为1.6、7.2、65 nmol/L；对D2受体的亲和常数分别为1920、5320和9800 nmol/L；对D3受体的亲和常数分别为1710、4270和5600 nmol/L。结果表明，3-(4-苄基哌嗪-1-基甲基)吡唑并[1,5-α]吡啶对多巴胺D4受体具有较高的亲和性与选择性，是多巴胺D4受体潜在的配基。

Synthesis and in vitro Receptor Binding Assay of Pyrazolo[1,5-α]pyridines

3-(4-Benzylpiperazin-1-ylmethyl)pyrazolo[1,5-α]pyridine, 3-[4-(4-chlorobenzyl) piperazin-1-ylmethyl]pyrazolo-[1,5-α]pyridine and 3-[4-(4-methoxybenzyl)piperazin-1-ylmethyl] pyrazolo[1,5-a]pyridine were synthesized from pyrazolo[1,5-α]pyridine-3-carbaldehyde and 1-piperazinearboxaldehyde through reductive amination, amide hydrolysis and N-alkylation. The structures of the intermediates and the target compounds were confirmed by 1H NMR and ESI MS. Through in vitro receptor binding assay, the affinity constants(Ki) of the target compounds were determined to be 1.6, 7.2, 65 nmol/L for D4 receptor; 1920, 5320, 9800 nmol/L for D2 receptor; 1710, 4270 and 5600 nmol/L for dopamine D3 receptor, respectively. The results suggested that 3-(4-benzylpiperazin-1-ylmethyl)pyrazolo[1,5-α] pyridine is a potential dopamine D4 receptor ligand.