[3H]N-[4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)butyl]-2-methoxy-5-methylbenzamide: a novel sigma-2 receptor probe

Eur J Pharmacol. 2005 Nov 21;525(1-3):8-17. doi: 10.1016/j.ejphar.2005.09.063. Epub 2005 Nov 10.


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 (sigma2) receptors was evaluated in vitro. [3H]RHM-1 was found to have a higher affinity for sigma2 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 K(off) rate since both radioligands have similar K(on) rates. Competitive binding assays were also conducted using a panel of compounds with known affinity for sigma2 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 sigma2 receptors in vitro.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Benzamides / metabolism*
  • Binding, Competitive
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Humans
  • In Vitro Techniques
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, sigma / metabolism*
  • Transplantation, Heterologous
  • Tritium


  • Benzamides
  • N-(2-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)ethyl)-2-methoxy-5-methylbenzamide
  • N-(4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)butyl)-2-methoxy-5-methyl-benzamide
  • Receptors, sigma
  • sigma-2 receptor
  • Tritium