TY - JOUR
T1 - Synthesis and in vitro evaluation of tetrahydroisoquinolinyl benzamides as ligands for σ receptors
AU - Xu, Rong
AU - Lever, John R.
AU - Lever, Susan Z.
N1 - Funding Information:
We thank the National Cancer Institute (P50 CA 103130: Center for Single Photon-Emitting Cancer Imaging Agents) for partial support of this research. We also acknowledge facilities provided by Truman Memorial Veterans’ Hospital, and NSF CHE-95-31247 and NIH 1S10RR11962-01 grant awards for NMR instrumentation.
PY - 2007/5/1
Y1 - 2007/5/1
N2 - 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 σ2 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 σ2 affinity by 8- to 12-fold, with no major differences noted with ring size. By contrast, the methylenedioxy analog showed a 10-fold greater σ1 affinity than 1, and progressively lower σ1 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 σ receptor binding. The σ2 affinity of the open-ring compound decreased by 1700-fold, while σ1 affinity was not changed. Thus, a constrained tetrahydroisoquinoline ring system is key to the exceptional σ2 receptor binding affinity and selectivity of this active series.
AB - 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 σ2 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 σ2 affinity by 8- to 12-fold, with no major differences noted with ring size. By contrast, the methylenedioxy analog showed a 10-fold greater σ1 affinity than 1, and progressively lower σ1 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 σ receptor binding. The σ2 affinity of the open-ring compound decreased by 1700-fold, while σ1 affinity was not changed. Thus, a constrained tetrahydroisoquinoline ring system is key to the exceptional σ2 receptor binding affinity and selectivity of this active series.
KW - Tetrahydroisoquinoline
KW - σ Receptors
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U2 - 10.1016/j.bmcl.2007.02.005
DO - 10.1016/j.bmcl.2007.02.005
M3 - Article
C2 - 17317173
AN - SCOPUS:33947730361
VL - 17
SP - 2594
EP - 2597
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 9
ER -