Wu Zong-Wen, Song Shu-Yong, Li Li, Lu He-Lin, Lieberman Brian, Huang Yun-Sheng, Mach Robert H
School of Pharmacy, Guangdong Medical College, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China.
Department of Radiology, University of Pennsylvania, 231 S. 34th St, Philadelphia, PA 19104, USA.
Bioorg Med Chem. 2015 Apr 1;23(7):1463-71. doi: 10.1016/j.bmc.2015.02.012. Epub 2015 Feb 16.
A series of tetrahydroindazole derivatives were synthesized and evaluated for their affinities for both sigma-1 and sigma-2 receptors. These compounds are hybrid structures of a tetrahydroindazole substituted benzamide and a 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety or a 9-azabicyclo[3.3.1]nonan-3-yl-amine moiety. These newly synthesized hybrid analogs showed various affinities for sigma-2 receptor without any significant affinities for sigma-1 receptor. In particular, compounds 12, 15b, 15c, and 15d, demonstrated moderate affinity and excellent selectivity for sigma-2 receptor. It is interesting to note that 3-5 carbon units between the tetrahydroindazole substituted benzamide and the 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety are appropriate for sigma-2 receptor binding. No substitution on the 9-aza nitrogen is proper for sigma-2 affinity in the 2-(9-azabicyclo[3.3.1]nonan-3-yl-amino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide analogs.
合成了一系列四氢吲唑衍生物，并评估了它们对σ-1和σ-2受体的亲和力。这些化合物是四氢吲唑取代苯甲酰胺与6,7-二甲氧基-1,2,3,4-四氢异喹啉部分或9-氮杂双环[3.3.1]壬烷-3-基胺部分的杂化结构。这些新合成的杂化类似物对σ-2受体表现出不同的亲和力，而对σ-1受体没有任何显著亲和力。特别是，化合物12、15b、15c和15d对σ-2受体表现出中等亲和力和优异的选择性。值得注意的是，四氢吲唑取代苯甲酰胺与6,7-二甲氧基-1,2,3,4-四氢异喹啉部分之间的3至5个碳单元适合与σ-2受体结合。在2-(9-氮杂双环[3.3.1]壬烷-3-基氨基)-4-(3,6,6-三甲基-4-氧代-4,5,6,7-四氢-1H-吲唑-1-基)苯甲酰胺类似物中，9-氮杂氮上无取代基对σ-2亲和力是合适的。
