Binding profiles and physical dependence liabilities of selected benzodiazepine receptor ligands.
In vitro binding profiles were determined for selected benzodiazepine receptor (BZR) ligands by quantitative radioautography in rat brain. The ligands represent subtype-selective agonists (zolpidem) or nonselective BZR agonists (diazepam), as well as BZR partial agonists (bretazenil, Ro 43-9624, and Ro 19-8022). In addition, these compounds were evaluated in a precipitated withdrawal paradigm in monkeys. The physical dependence liability was not clearly related to the in vitro brain BZR binding profiles of these compounds. Therefore, diazepam, bretazenil, Ro 19-8022, and Ro 43-9624 had regional affinities for the 13 selected rat brain regions that were close to the mean values across regions, despite the clearly greater physical dependence potential of diazepam. Zolpidem, on the other hand, had regional affinities for the 13 rat brain regions that diverged significantly from the mean value across regions and exhibited a lower physical dependence potential than diazepam. These results raise the possibility that a combination of BZR subtype selectivity with partial agonism could yield a marked reduction of physical dependence liability.
Richards
J G
JG
Pharma Division, Preclinical CNS Research, F. Hoffman-La Roche Ltd., Basel, Switzerland. j_grayson.richards@roche.com@internet
Martin
J R
JR
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001569:Benzodiazepines; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D003220:Conflict, Psychological; D004435:Eating / Q000187:drug effects / Q000502:physiology; D018757:GABA Modulators / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D004856:Postural Balance / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D012453:Saimiri; D013329:Structure-Activity Relationship; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology; D019966:Substance-Related Disorders / Q000503:physiopathology*
D014151:Anti-Anxiety Agents; D018757:GABA Modulators; D008024:Ligands; D011963:Receptors, GABA-A; D001569:Benzodiazepines