[3H]BHDP as a novel and selective ligand for sigma1 receptors in liver mitochondria and brain synaptosomes of the rat.
The binding profile of [(3)H]BHDP ([(3)H]N-benzyl-N'-(2-hydroxy-3,4-dimethoxybenzyl)-piperazine) was evaluated. [(3)H]BHDP labelled a single class of binding sites with high affinity (K(d)=2-3 nM) in rat liver mitochondria and synaptic membranes. The pharmacological characterization of these sites using sigma reference compounds revealed that these sites are sigma receptors and, more particularly, sigma1 receptors. Indeed, BHDP inhibited [(3)H]pentazocine binding, a marker for sigma1 receptors, with high affinity in a competitive manner. BHDP is selective for sigma1 receptors since it did not show any relevant affinity for most of the other receptors, ion channels or transporters tested. Moreover, in an in vitro model of cellular hypoxia, BHDP prevented the fall in adenosine triphosphate (ATP) levels caused by 24 h hypoxia in cultured astrocytes. Taken together, these results demonstrate that [(3)H]BHDP is a potent and selective ligand for sigma1 receptors showing cytoprotective effects in astrocytes.
Klouz
Anis
A
Laboratoire de Pharmacologie, EA427, Faculté de Médecine, Créteil, France.
Tillement
Jean-Paul
JP
Boussard
Marie-Françoise
MF
Wierzbicki
Michel
M
Berezowski
Vincent
V
Cecchelli
Roméo
R
Labidalle
Serge
S
Onténiente
Brigitte
B
Morin
Didier
D
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000378:metabolism; D008024:Ligands; D008930:Mitochondria, Liver / Q000378:metabolism*; D010879:Piperazines / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D013379:Substrate Specificity; D013574:Synaptosomes / Q000378:metabolism*; D013997:Time Factors; D014316:Tritium / Q000378:metabolism
D008024:Ligands; D010879:Piperazines; D017480:Receptors, sigma; D014316:Tritium; D000255:Adenosine Triphosphate