Solvay Pharmaceuticals, Research Laboratories, C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
J Med Chem. 2010 Feb 11;53(3):1338-46. doi: 10.1021/jm901614b.
Pyrazolines 7-10 were designed as novel CB(1) receptor antagonists, which exhibited improved turbidimetric aqueous solubilities. On the basis of their extended CB(1) antagonist pharmacophore, hybrid molecules exhibiting cannabinoid CB(1) receptor antagonistic as well as acetylcholinesterase (AChE) inhibiting activities were designed. The target compounds 12, 13, 20, and 21 are based on 1 (tacrine) as the AChE inhibitor (AChEI) pharmacophore and two different CB(1) antagonistic pharmacophores. The imidazole-based 20 showed high CB(1) receptor affinity (48 nM) in combination with high CB(1)/CB(2) receptor subtype selectivity (>20-fold) and elicited equipotent AChE inhibitory activity as 1. Molecular modeling studies revealed the presence of a binding pocket in the AChE enzyme which nicely accommodates the CB(1) pharmacophores of the target compounds 12, 13, 20, and 21.
吡唑啉类化合物 7-10 被设计为新型 CB(1)受体拮抗剂，具有改善的浊度水溶解度。基于它们扩展的 CB(1)拮抗剂药效团，设计了同时具有大麻素 CB(1)受体拮抗作用和乙酰胆碱酯酶 (AChE) 抑制活性的混合分子。目标化合物 12、13、20 和 21 基于 1（他克林）作为 AChE 抑制剂（AChEI）药效团和两种不同的 CB(1)拮抗药效团。基于咪唑的 20 显示出高的 CB(1)受体亲和力（48 nM），与高 CB(1)/CB(2)受体亚型选择性（>20 倍）相结合，并表现出与 1 相当的 AChE 抑制活性。分子模拟研究表明，AChE 酶中存在一个结合口袋，可以很好地容纳目标化合物 12、13、20 和 21 的 CB(1)药效团。
