Regulation of sigma-receptors: high- and low-affinity agonist states, GTP shifts, and up-regulation by rimcazole and 1,3-Di(2-tolyl)guanidine

J Neurochem. 1989 Sep;53(3):779-88. doi: 10.1111/j.1471-4159.1989.tb11773.x.


The regulation of the central sigma-binding site was investigated using both in vitro and in vivo manipulations in conjunction with radioligand binding. The displacement of the binding of R(+)-[3H]3-[3-hydroxyphenyl]-N-(1-propyl)piperidine [R(+)-[3H]3-PPP] to cortical homogenates by a range of drugs was consistent with the site labelled being a sigma-receptor. (+)-SKF 10,047, (-)-SKF 10,047, (+/-)-cyclazocine, phencyclidine, and dexoxadrol displaced R(+)-[3H]3-PPP with pseudo-Hill coefficients of less than 1. Further analysis employing nonlinear curve fitting techniques demonstrated that displacement data for these compounds were described better by a model whereby R(+)-[3H]3-PPP was displaced from two discrete sites; approximately 65% of the total sites were in the high-affinity state. In the presence of 10 mM Mg2+ and 0.3 mM GTP, displacement curves for (+)-SKF 10,047 and (+/-)-cyclazocine were shifted to the right. These findings were due to the shift of some 15% of the high-affinity binding sites to a low-affinity state. Saturation experiments revealed that 0.3 mM GTP acted competitively to decrease the affinity of R(+)-[3H]3-PPP for the sigma sites. The sigma-binding site was thus likely to be linked to a guanine nucleotide regulatory (G) protein. Thus sigma drugs could be subdivided on the basis of their GTP sensitivity and pseudo-Hill coefficients, and by analogy with other receptors R(+)-3-PPP, (+)-SKF 10,047, and (+/-)-cyclazocine, may be putative sigma-agonists. 1,3-Di(2-tolyl)guanidine (DTG), rimcazole, and haloperidol displaced R(+)-[3H]3-PPP with pseudo-Hill coefficients of approximately unity and thus may be sigma-antagonists. Subchronic treatment with rimcazole was characterized by slight sedation and a concomitant up-regulation, with a decrease in the affinity, of sigma-binding sites. The schedule of rimcazole also increased dopamine turnover in the nucleus accumbens; both the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC) and the DOPAC/dopamine ratio were elevated. DTG produced similar alterations to the binding parameters of the sigma-binding site; however, changes were not observed in general behavior or accumbal dopamine turnover. sigma-Receptors are likely to be linked to a G protein and are functionally involved in the CNS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3,4-Dihydroxyphenylacetic Acid / metabolism
  • Animals
  • Binding, Competitive
  • Brain / metabolism*
  • Carbazoles / pharmacology*
  • Cyclazocine / metabolism
  • Dopamine / metabolism
  • Dopamine Agents
  • GTP-Binding Proteins / metabolism
  • Guanidines / pharmacology*
  • Guanosine Triphosphate / pharmacology*
  • Magnesium / pharmacology
  • Male
  • Phenazocine / analogs & derivatives
  • Phenazocine / pharmacology
  • Rats
  • Rats, Inbred Strains
  • Receptors, Opioid / drug effects
  • Receptors, Opioid / metabolism*
  • Receptors, sigma


  • Carbazoles
  • Dopamine Agents
  • Guanidines
  • Receptors, Opioid
  • Receptors, sigma
  • 3,4-Dihydroxyphenylacetic Acid
  • SK&F 10047
  • Guanosine Triphosphate
  • rimcazole
  • GTP-Binding Proteins
  • Magnesium
  • Phenazocine
  • Cyclazocine
  • 1,3-ditolylguanidine
  • Dopamine