[3H]Alnespirone: a novel specific radioligand of 5-HT1A receptors in the rat brain.
Determination of the optimal assay conditions for the specific binding of a tritiated derivative of the novel potential anxiolytic drug alnespirone (S-20499, (+)-4-[N-(5-methoxy-chroman-3-yl)-N-propylamino]butyl-8-azaspiro-( 4,5)-decane-7,9-dione) allowed the demonstration that this radioligand bound with a high affinity (Kd = 0.36 nM) to a homogeneous class of sites in rat hippocampal membranes. The pharmacological properties of [3H]alnespirone specific binding sites matched exactly (r = 0.95) those of 5-HT1A receptors identified with [3H]8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) as radioligand. Furthermore, membrane binding experiments and autoradiographic labeling of tissue sections showed that the regional distribution of [3H]alnespirone specific binding sites in the rat brain and spinal cord superimposed over that of 5-HT1A receptors specifically labeled by [3H]8-OH-DPAT. However, the differential sensitivity of [3H]alnespirone and [3H]8-OH-DPAT specific binding to various physicochemical effectors (temperature, pH, Mn2+, N-ethyl-maleimide) supports the idea that these two agonist radioligands did not recognize 5-HT1A receptors exactly in the same way. These differences probably account for the reported inability of alnespirone, in contrast to 8-OH-DPAT, to induce some 5-HT1A receptor-mediated behavioural effects in rats.
Fabre
V
V
INSERM U.288, NeuroPsychoPharmacologie, Faculté de Médecine Pitié-Salpêtrière, Paris, France.
Boni
C
C
Mocaër
E
E
Lesourd
M
M
Hamon
M
M
Laporte
A M
AM
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism*; D001345:Autoradiography; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D002712:Chlorides / Q000494:pharmacology; D005033:Ethylmaleimide / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008297:Male; D017895:Manganese Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000378:metabolism*; D013141:Spiro Compounds / Q000378:metabolism*; D013696:Temperature
D014151:Anti-Anxiety Agents; D002712:Chlorides; D008024:Ligands; D017895:Manganese Compounds; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D013141:Spiro Compounds; C075319:alnespirone; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D006160:Guanosine Triphosphate; D005033:Ethylmaleimide; C025340:manganese chloride