Synthesis and evaluation of tetrahydroindazole derivatives as sigma-2 receptor ligands

Bioorganic & Medicinal Chemistry
Zong-Wen WuRobert H Mach

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, 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.

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Citations

Jun 1, 2017·Proceedings of the National Academy of Sciences of the United States of America·Assaf AlonAndrew C Kruse
Dec 19, 2017·Acta Crystallographica. Section E, Crystallographic Communications·Anatoly MishnevMāris Turks
Mar 23, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hamad M Al-MatarMona A Shalaby
Oct 14, 2020·European Journal of Medicinal Chemistry·Xiao-Yang XieYun-Sheng Huang
Apr 29, 2021·Expert Opinion on Drug Discovery· FaheemSankaranarayanan Murugesan
Aug 25, 2020·ACS Medicinal Chemistry Letters·Daniel A GreenfieldAndrew C Kruse

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