Synthesis and evaluation of tetrahydroindazole derivatives as sigma-2 receptor ligands.
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.
School of Pharmacy, Guangdong Medical College, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China.
Zong-Wen
ZW
Wu
School of Pharmacy, Guangdong Medical College, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China.
Shu-Yong
SY
Song
School of Pharmacy, Guangdong Medical College, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China.
Li
L
Li
School of Pharmacy, Guangdong Medical College, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China.
He-Lin
HL
Lu
Department of Radiology, University of Pennsylvania, 231 S. 34th St, Philadelphia, PA 19104, USA.
Brian
B
Lieberman
School of Pharmacy, Guangdong Medical College, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, Guangdong 523808, China. Electronic address: yshuang@gdmc.edu.cn.
Yun-Sheng
YS
Huang
Department of Radiology, University of Pennsylvania, 231 S. 34th St, Philadelphia, PA 19104, USA. Electronic address: rmach@mail.med.upenn.edu.
Robert H
RH
Mach
D000818:Animals; D001921:Brain / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006168:Guinea Pigs; D007191:Indazoles / Q000138:chemical synthesis* / Q000378:metabolism*; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000378:metabolism*
D007191:Indazoles; D008024:Ligands; D017480:Receptors, sigma; C106107:sigma-2 receptor
Affinity; Ligands; Sigma receptor; Synthesis; Tetrahydroindazole