TY - JOUR
T1 - [3H]N-[4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)butyl]- 2-methoxy-5-methylbenzamide
T2 - A novel sigma-2 receptor probe
AU - Xu, Jinbin
AU - Tu, Zhude
AU - Jones, Lynne A.
AU - Vangveravong, Suwanna
AU - Wheeler, Kenneth T.
AU - Mach, Robert H.
PY - 2005/11/21
Y1 - 2005/11/21
N2 - N-[4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)butyl] -2-methoxy-5-methyl-benzamide (RHM-1) and N-[2-(3,4-dihydro-6,7- dimethoxyisoquinolin-2(1H)-yl)ethyl]-2-methoxy-5-methylbenzamide (RHM-2), two conformationally flexible benzamide analogues, were radiolabeled with tritium (specific activity = 80 Ci/mmol) and the binding of [3H]RHM-1 and [3H]RHM-2 to sigma-2 (σ2) receptors was evaluated in vitro. [3H]RHM-1 was found to have a higher affinity for σ2 receptors compared to [3H]RHM-2 and [ 3H]1,3-di-o-tolylguanidine ([3H]DTG). [3H]RHM-1 had a dissociation constant (Kd) of 0.66 ± 0.12 nM in rat liver membrane homogenates, which was 30-fold higher than that of [ 3H]RHM-2 (Kd = 19.48 ± 0.51 nM). The lower affinity of [3H]RHM-2 can be attributed to its faster Koff rate since both radioligands have similar Kon rates. Competitive binding assays were also conducted using a panel of compounds with known affinity for σ2 receptors. The pharmacologic profile of [3H]RHM-1 was in agreement with that of [3H]DTG. The results of this study indicate that [3H]RHM-1 is a useful ligand for studying σ2 receptors in vitro.
AB - N-[4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)butyl] -2-methoxy-5-methyl-benzamide (RHM-1) and N-[2-(3,4-dihydro-6,7- dimethoxyisoquinolin-2(1H)-yl)ethyl]-2-methoxy-5-methylbenzamide (RHM-2), two conformationally flexible benzamide analogues, were radiolabeled with tritium (specific activity = 80 Ci/mmol) and the binding of [3H]RHM-1 and [3H]RHM-2 to sigma-2 (σ2) receptors was evaluated in vitro. [3H]RHM-1 was found to have a higher affinity for σ2 receptors compared to [3H]RHM-2 and [ 3H]1,3-di-o-tolylguanidine ([3H]DTG). [3H]RHM-1 had a dissociation constant (Kd) of 0.66 ± 0.12 nM in rat liver membrane homogenates, which was 30-fold higher than that of [ 3H]RHM-2 (Kd = 19.48 ± 0.51 nM). The lower affinity of [3H]RHM-2 can be attributed to its faster Koff rate since both radioligands have similar Kon rates. Competitive binding assays were also conducted using a panel of compounds with known affinity for σ2 receptors. The pharmacologic profile of [3H]RHM-1 was in agreement with that of [3H]DTG. The results of this study indicate that [3H]RHM-1 is a useful ligand for studying σ2 receptors in vitro.
KW - Benzamide
KW - Breast tumor
KW - Radioligand binding
KW - σ receptor
UR - http://www.scopus.com/inward/record.url?scp=28044445696&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2005.09.063
DO - 10.1016/j.ejphar.2005.09.063
M3 - Article
C2 - 16289030
AN - SCOPUS:28044445696
VL - 525
SP - 8
EP - 17
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 1-3
ER -