In vivo determination of the profile of benzodiazepine ligands by comparing the inhibition of 3H-Ro 15-1788 binding to the modulation of cGMP levels in mouse cerebellum.
The in vivo effects of various benzodiazepine (BZD) ligands belonging to different chemical families were studied comparatively in mouse cerebellum using displacement of 3H-Ro 15-1788 binding and cGMP content as biochemical tools. It was possible to differentiate four classes of compounds with regard to these biochemical parameters. The first class of compounds such as diazepam and suriclone induced a net effect on in vivo 3H-Ro 15-1788 binding and a dose-dependent decrease of cGMP levels. A second class of drugs such as ZK 91296 and CGS 9896 showed in vivo activities in displacement studies but relatively small or moderate activities on cGMP levels. A third class was represented by Ro 15-1788 itself which prevented dose-dependently the in vivo 3H-Ro 15-1788 binding but was devoid of effect on cGMP levels. Finally, a fourth class of compounds (CGS 8216, FG 7142, beta-CCM and DMCM) showed in vivo displacement of 3H-Ro 15-1788 with concomitant increase of cGMP levels. The first class of compounds represents full agonists, the second class, partial agonists, the third class, the antagonist Ro-15-1788 itself, and the fourth class corresponds to inverse agonists. Thus it is proposed to use 3H-Ro 15-1788 binding and cGMP levels to differentiate in vivo BZD ligands acting on the BZD receptor/GABA receptor/chloride ionophore complex.
Boireau
A
A
Rhône-Poulenc Santé, Centre de recherches de Vitry, Vitry-sur-Seine, France.
Martel
M
M
Farges
G
G
Dubédat
P
P
Laduron
P M
PM
Blanchard
J C
JC
D000818:Animals; D002531:Cerebellum / Q000378:metabolism*; D006152:Cyclic GMP / Q000032:analysis*; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008024:Ligands; D008297:Male; D051379:Mice; D009287:Naphthyridines; D010879:Piperazines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects*; D013457:Sulfur Compounds; D014316:Tritium
D008024:Ligands; D009287:Naphthyridines; D010879:Piperazines; D011963:Receptors, GABA-A; D013457:Sulfur Compounds; D014316:Tritium; D005442:Flumazenil; D006152:Cyclic GMP; C037283:suriclone; D003975:Diazepam