Synthesis and in vitro evaluation of tetrahydroisoquinolinyl benzamides as ligands for sigma receptors.
5-Bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxy-benzamide (1) is one of the most potent and selective sigma(2) receptor ligands reported to date. Previous structure-activity relationship studies of such tetrahydroisoquinolinyl benzamides have focused on the linker that connects the ring systems and the effects of benzamide ring substituents. The present study explores the effects of fusing methylene-, ethylene-, and propylenedioxy rings onto the tetrahydroisoquinoline in place of the two methoxy groups. These modifications decreased sigma(2) affinity by 8- to 12-fold, with no major differences noted with ring size. By contrast, the methylenedioxy analog showed a 10-fold greater sigma(1) affinity than 1, and progressively lower sigma(1) affinities were then noted with increasing ring size. We also opened the tetrahydroisoquinoline ring of 1 to study the effects of greater conformational fluidity on sigma receptor binding. The sigma(2) affinity of the open-ring compound decreased by 1700-fold, while sigma(1) affinity was not changed. Thus, a constrained tetrahydroisoquinoline ring system is key to the exceptional sigma(2) receptor binding affinity and selectivity of this active series.
Xu
Rong
R
Department of Chemistry, University of Missouri-Columbia, Columbia, MO, USA.
Lever
John R
JR
Lever
Susan Z
SZ
D000475:Alkenes / Q000737:chemistry; D001549:Benzamides / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005030:Ethylenes / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008968:Molecular Conformation; D011485:Protein Binding; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000475:Alkenes; D001549:Benzamides; D005030:Ethylenes; D008024:Ligands; D017480:Receptors, sigma; C106107:sigma-2 receptor; C036216:ethylene; C013658:propylene