Benzodiazepine receptor binding of nonbenzodiazepines in vivo: alpidem, zolpidem and zopiclone.
Several classes of nonbenzodiazepine compounds, including imidazopyridines such as alpidem and zolpidem and cyclopyrrolones, e.g., zopiclone, have effects similar to benzodiazepines and may act at the benzodiazepine receptor in brain. We characterized the binding of these compounds to the benzodiazepine site in three brain regions using specific uptake of the high-affinity ligand [3H]Ro15-1788 (flumazenil). For alpidem, benzodiazepine binding was decreased in cortex and hippocampus with increasing drug dose. For zolpidem, receptor binding was reduced in cortex without a dose-response effect and no effect was observed on cerebellar binding. Zopiclone did not alter binding except for a decrease in binding at the lowest dose evaluated and an increase in binding above control at the highest dose. These data corroborate prior studies indicating that the imidazopyridines appear to act at the benzodiazepine receptor, but do not support receptor subtype selectivity of zolpidem. The limited effect of zopiclone except for increased binding at high doses is also consistent with prior studies suggesting that zopiclone acts at a site distinct from the benzodiazepine receptor.
Department of Pharmacology and Experimental Therapeutics and Psychiatry, Tufts University School of Medicine, Boston, MA.
J J
JJ
Byrnes
D J
DJ
Greenblatt
L G
LG
Miller
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values; D000077334:Zolpidem
D014151:Anti-Anxiety Agents; D053961:Azabicyclo Compounds; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D010879:Piperazines; D011725:Pyridines; D011963:Receptors, GABA-A; C515050:zopiclone; D005442:Flumazenil; D000077334:Zolpidem; C052036:alpidem