In recent years a number of novel compounds have been described with affinity and specificity for BZ (omega) receptors. While some of these agents appear to act, like benzodiazepines themselves, as full agonists at different receptor subtypes (e.g. suriclone), several non-selective partial agonists (e.g. bretazenil) have been described, as have a number of BZ(1) (omega(1)) selective drugs (e.g. zolpidem). Previous work has reported a number of differences between the behavioural effects of some of these drugs and those of benzodiazepines; however, very few studies have attempted systematic comparisons of a large number of drugs in different procedures. In the present study a wide range of BZ (omega) receptor ligands was studied using two behavioural methods in rats: unpunished and punished food-reinforced operant responding and the discriminative stimulus effects of pentylenetetrazole. Punished operant responding showed increases with the benzodiazepines, chlordiazepoxide and clorazepate, the non-benzodiazepines, saripidem, CL 273,547 and F 2692 (limited effect at a single dose) and the partial agonists bretazenil and Ro 19-8022, but the BZ(1) selective agents, alpidem, abecarnil and CL 284,846, did not increase rates of punished operant responding. Rates of unpunished responding were decreased by higher doses of all drugs except bretazenil and Ro 19-8022. Dose-related antagonism of the pentylenetetrazole (18mg/kg) discriminative stimulus was produced by several benzodiazepines, by the partial agonists bretazenil, Ro 19-8022 and divaplon, and by suriclone, saripidem and CL 273,547. The BZ(1) (omega(1)) selective drugs abecarnil, CL 284,846, zolpidem, CL 218,872 and alpidem were also active in blocking pentylenetetrazole but produced only partial antagonism which was not clearly dose-related. The results show that novel BZ (omega) receptor ligands do not always produce a behavioural profile identical to that shown by benzodiazepines. In particular, BZ(1) (omega(1)) selective drugs do not give rise to clear increases in punished operant responding and have only limited efficacy in blocking the pentylenetetrazole cue. These effects may be due to the marked propensity of BZ(1) (omega(1)) selective drugs to decrease operant response rates.

01 May 1994·Pharmacology Biochemistry and BehaviorQ4 · PSYCHOLOGY

F 2692: Flumazenil-reversible anxiolytic effects but inactive on [3H]-Ro 15-4513 binding

Q4 · PSYCHOLOGY

Article

Author: Andrews, Nick ; File, Sandra E.

F 2692, a pyridazine derivative, has little affinity for benzodiazepine receptors, yet in two animal tests its anxiolytic effects have been reported to be reversed by benzodiazepine antagonists. In the rat social interaction test, after 5 days of IP treatment, F 2692 (3, 10, or 30 mg/kg) produced greater increases in social interaction than diazepam (0.3, 1, or 3 mg/kg). A comparison of acute and 5 day administration of F 2692 showed rapidly developing tolerance at all doses. The acute anxiolytic effects of F 2692 (1 mg/kg) were reversed by the benzodiazepine antagonists flumazenil (4 mg/kg) and ZK 93426 (4 mg/kg). We, therefore, examined whether F 2692 was active at a benzodiazepine binding site (the diazepam-insensitive portion of [3H]-Ro 15-4513) to which flumazenil but not flunitrazepam binds. However, F 2692 (10(-9) to 10(-4) M) was without effect on this binding. Thus, F 2692 has anxiolytic actions in the social interaction test, that are greater than those of diazepam, and which can be reversed by benzodiazepine antagonists. However, the site of action of the compound remains unknown.

01 Jan 1993·PsychopharmacologyQ3 · MEDICINE

2. Evaluation of its tolerance and dependence producing potential and of its effects on benzodiazepine withdrawal in the elevated plus-maze test in rats

Q3 · MEDICINE

Article

Author: Chopin, Philippe ; Briley, Mike ; Assie, Marie Bernadette

After 21 days administration, diazepam (0.3-3 mg/kg/day) exhibited, 30 min after the last injection, tolerance to the sedative effect and "anxiolytic" activity as recorded in the elevated plus-maze test in rats. A dose-dependent increase of "anxiety" was also observed 24 h after withdrawal from 21 or 90 days of diazepam treatment. In contrast, under the same experimental conditions, F 2692 [1-(3'-trifluoromethyl phenyl) 1,4-dihydro 3-amino 4-oxo 6-methyl pyridazine] (3-30 mg/kg/day) exhibited no tolerance to either the sedative effect or the "anxiolytic" activity and showed no "anxiogenic rebound" response after withdrawal. Chronic diazepam pretreatment for 21 days modified neither the sedative effect nor the dose-dependent "anxiolytic" effect of F 2692. Furthermore, F 2692 could reverse the anxiogenic response after withdrawal from 21 days administration of diazepam. Finally, administration of diazepam for 3 weeks followed by a daily administration of F 2692 for a week induced no increase of "anxiety" 24 h after withdrawal.

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Indication	Highest Phase	Country/Location	Organization	Date
Anxiety Disorders	Phase 1	FR	Pierre Fabre SA	-
Anxiety Disorders	Phase 1	-	Pierre Fabre SA	-

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