Pharmaceutical Chemistry I, Pharmaceutical Institute, PharmaCenter Bonn, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
J Med Chem. 2012 Sep 27;55(18):7967-77. doi: 10.1021/jm3008213. Epub 2012 Sep 11.
A series of 7-alkyl-3-benzylcoumarins was designed, synthesized, and tested at cannabinoid CB(1) and CB(2) receptors in radioligand binding and cAMP accumulation studies. 7-Alkyl-3-benzylcoumarins were found to constitute a versatile scaffold for obtaining potent CB receptor ligands with high potency at either CB(1) or CB(2) and a broad spectrum of efficacies. Fine-tuning of compound properties was achieved by small modifications of the substitution pattern. The most potent compounds of the present series include 5-methoxy-3-(2-methylbenzyl)-7-pentyl-2H-chromen-2-one (19a, PSB-SB-1201), a selective CB(1)antagonist (K(i) CB(1) 0.022 μM), 5-methoxy-3-(2-methoxybenzyl)-7-pentyl-2H-chromen-2-one (21a, PSB-SB-1202), a dual CB(1)/CB(2)agonist (CB(1)K(i) 0.032 μM, EC(50) 0.056 μM; CB(2)K(i) 0.049 μM, EC(50) 0.014 μM), 5-hydroxy-3-(2-hydroxybenzyl)-7-(2-methyloct-2-yl)-2H-chromen-2-one (25b, PSB-SB-1203), a dual CB(1)/CB(2) ligand that blocks CB(1) but activates CB(2) receptors (CB(1)K(i) 0.244 μM; CB(2)K(i) 0.210 μM, EC(50) 0.054 μM), and 7-(1-butylcyclopentyl)-5-hydroxy-3-(2-hydroxybenzyl)-2H-chromen-2-one (27b, PSB-SB-1204), a selective CB(2) receptor agonist (CB(1)K(i) 1.59 μM; CB(2)K(i) 0.068 μM, EC(50) 0.048 μM).
设计、合成并测试了一系列 7-烷基-3-苄基香豆素，在放射性配体结合和 cAMP 积累研究中在大麻素 CB(1)和 CB(2)受体上进行了测试。7-烷基-3-苄基香豆素被发现是获得具有高 CB(1)或 CB(2)效力和广泛效力的高效大麻素受体配体的多功能支架。通过对取代模式的微小修改来实现化合物性质的微调。本系列中最有效的化合物包括 5-甲氧基-3-(2-甲基苄基)-7-戊基-2H-色烯-2-酮（19a，PSB-SB-1201），一种选择性 CB(1)拮抗剂（Ki CB(1)0.022 μM），5-甲氧基-3-(2-甲氧基苄基)-7-戊基-2H-色烯-2-酮（21a，PSB-SB-1202），一种双重 CB(1)/CB(2)激动剂（CB(1)Ki 0.032 μM，EC(50)0.056 μM；CB(2)Ki 0.049 μM，EC(50)0.014 μM），5-羟基-3-(2-羟基苄基)-7-(2-甲基辛基-2-基)-2H-色烯-2-酮（25b，PSB-SB-1203），一种阻断 CB(1)但激活 CB(2)受体的双重 CB(1)/CB(2)配体（CB(1)Ki 0.244 μM；CB(2)Ki 0.210 μM，EC(50)0.054 μM），和 7-(1-丁基环戊基)-5-羟基-3-(2-羟基苄基)-2H-色烯-2-酮（27b，PSB-SB-1204），一种选择性 CB(2)受体激动剂（CB(1)Ki 1.59 μM；CB(2)Ki 0.068 μM，EC(50)0.048 μM）。
