Anticonvulsant, anxiolytic, and non-sedating actions of imidazenil and other imidazo-benzodiazepine carboxamide derivatives.
Recent evidence suggests that alpha1-containing GABA(A) receptors mediate the sedative, amnestic, and to some extent the anticonvulsant actions of non-selective benzodiazepine (BZ) receptor ligands, such as diazepam (DZ). Anxiolytic and in part, anticonvulsant actions of BZ ligands are mediated by alpha2-, alpha3-, and alpha5-containing GABA(A) receptors. This has resulted in increasing interest in developing BZ ligands with selective actions at GABA(A) receptors, including alpha2-, alpha3-, and alpha5-subunits, but devoid of efficacy at alpha1-containing receptors. To refine their spectrum of pharmacological actions, efforts are being made to minimize unwanted effects such as sedation, amnesia, and tolerance liabilities. A prototype for such BZ ligands is imidazenil (IMD), an imidazo-benzodiazepine carboxylic acid derivative that elicits potent anticonvulsant and anxiolytic actions at doses virtually devoid of sedative, cardio-respiratory depressant and amnestic effects, and anticonvulsant tolerance liability. To define the pharmacological profile of IMD and its derivatives, we compared the anticonflict (anxiolytic), anti-proconflict (antipanic), anti-bicuculline (BIC), and maximal electroshock seizure (MES) effects, and the suppression of locomotor activity by imidazo-benzodiazepine carboxylic acid derivatives to those of DZ and bretazenil (BTZ). We report here that IMD and one of its derivatives (RO 25-2775) possess dose-dependent anticonflict, anti-proconflict, and anti-BIC actions but failed to suppress locomotor activity. Like DZ, the other IMD derivatives (enazenil, RO 25-2776, and RO 25-2847) not only elicit dose-dependent anticonflict, anti-proconflict, anti-BIC, anti-MES effects but also suppress locomotor activity. In contrast, none of the IMD derivatives studied shows any similarity to BTZ, which elicits anticonflict, anti-proconflict actions and suppresses locomotor activity but is virtually inactive against BIC-induced tonic-clonic convulsions.
Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA. jauta@psych.uic.edu
James
J
Auta
Bashkim
B
Kadriu
Pietro
P
Giusti
Erminio
E
Costa
Alessandro
A
Guidotti
D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism / Q000494:pharmacology*; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000378:metabolism / Q000494:pharmacology*; D001640:Bicuculline / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D006993:Hypnotics and Sedatives / Q000378:metabolism / Q000494:pharmacology; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010200:Panic / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011963:Receptors, GABA-A / Q000378:metabolism; D012137:Respiratory System / Q000187:drug effects
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D008024:Ligands; D021122:Protein Subunits; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C082661:imidazenil; D001640:Bicuculline