Synthesis and evaluation of tetrahydroindazole derivatives as sigma-2 receptor ligands. Issue 7 (1st April 2015)

• Record Type: Journal Article
• Authors: Wu, Zong-Wen; Song, Shu-Yong; Li, Li; Lu, He-Lin; Lieberman, Brian; Huang, Yun-Sheng; Mach, Robert H.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 7(2015)
• Page Start: 1463
• Page End: 1471
• Publication Date: 2015-04-01
• Subjects: Sigma receptor -- Synthesis -- Ligands -- Tetrahydroindazole -- Affinity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.02.012
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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, compounds12, 15b, 15c, and15d, 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-1 H -indazol-1-yl)benzamide analogs.