Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S Kingshighway Blvd, St Louis, MO 63110, USA.
Eur J Med Chem. 2011 Sep;46(9):3986-95. doi: 10.1016/j.ejmech.2011.05.072. Epub 2011 Jun 12.
A series of analogues were synthesized by optimizing the structure of papaverine. The in vitro PDE10A binding affinity (IC(50)) values for these new analogues were measured; for compounds that have IC(50) value less than 60 nM for PDE10A, the binding affinities (IC(50) value) for PDE3A and PDE3B were tested. Of these analogues, compounds 6a, 6b, 6n, 8b, 8c and 11 displayed relatively higher PDE10A potency with IC(50) value in the range of 28-60 nM. The most potent compound 1-(4-(2-(2-fluoroethoxy)ethoxy)-3-methoxybenzyl)-6,7-dimethoxyisoquinoline (8c) has the IC(50) value of 28 ± 1.2 nM for PDE10A, 2200 ± 437 nM for PDE3A and 2520 ± 210 nM for PDE3B. Compared to papaverine, compound 8c displayed similar PDE10A potency but improved selectivity to PDE10A versus PDE3A and PDE3B. To identify high potent PDE10A inhibitor, further optimization of the structures of these analogues is necessary.
通过优化罂粟碱的结构，合成了一系列类似物。测量了这些新类似物对 PDE10A 的体外结合亲和力（IC50 值）；对于 IC50 值小于 60 nM 的 PDE10A 的化合物，测试了它们对 PDE3A 和 PDE3B 的结合亲和力（IC50 值）。在这些类似物中，化合物 6a、6b、6n、8b、8c 和 11 对 PDE10A 的活性较高，IC50 值在 28-60 nM 范围内。最有效的化合物 1-(4-(2-(2-氟乙氧基)乙氧基)-3-甲氧基苄基)-6,7-二甲氧基异喹啉（8c）对 PDE10A 的 IC50 值为 28 ± 1.2 nM，对 PDE3A 的 IC50 值为 2200 ± 437 nM，对 PDE3B 的 IC50 值为 2520 ± 210 nM。与罂粟碱相比，化合物 8c 对 PDE10A 的活性相似，但对 PDE10A 相对于 PDE3A 和 PDE3B 的选择性更高。为了鉴定高效 PDE10A 抑制剂，有必要进一步优化这些类似物的结构。
