Pharmacological Characterization of the Novel Anxiolytic β-Carboline Abecarnil in Rodents and Primates

Abstract

ABSTRACT-~-Carboline abecarnil was behaviorally and biochemically characterized as a new anxiolytic agent in rodents and primates in comparison with the benzodiazepine (BZ) anxiolytics. Oral treatment with abecarnil (0.5 10 mg/kg) showed a potent anticonflict activity in the water-lick test in rats. The minimal effective dose was lower than those of BZ anxiolytics, such as etizolam, diazepam, clotiazepam and tofisopam. Abecarnil also showed taming effects to suppress fighting and aggressive behaviors in mice and monkeys with little sedative and ataxic effects, in contrast to the BZ anxiolytics producing marked sedative and ataxic effects. Furthermore, abecarnil suppressed both the sedative and ataxic effects induced by diazepam. Abecarnil bound to rat cerebellar BZ1 receptors (Ki=0.24 nM) with a higher affinity than to rat spinal cord BZ2 receptors (Ki=1.3 nM), whereas BZ derivatives bound to both the receptors with a low and equal affinity. GABA-ratios of abecarnil were 1.9 for the BZ, receptors and 2.8 for the BZ2 receptors, and they were smaller than those of diazepam and flunitrazepam. Thus, in contrast to the BZ derivatives, abecar nil may act as a selective partial agonist at central BZ, receptors, resulting in its potent anticonflict and tam ing effects with little sedative and ataxic effects.

Benzodiazepine-GABAA receptor complex ligands in two models of anxiety

“…This finding contrasts with the data obtained with diazepam and midazolam, and indicates that the role of differences in receptor affinity and/or efficacy of BDZ receptor ligands in changing animal behavior cannot be directly and unequivocally interpreted. In the case of abecarnil, its efficacy at some receptor subunit composition was reported to be low (Ozawa et al, 1994;Vorobjev et al, 1995). The drug shows some receptor subtype selectivity (Pribilla et al, 1993), which may limit its potency to disinhibit exploratory behavior, in our behavioral model.…”

A double-blind comparison of abecarnil and diazepam in the treatment of uncomplicated alcohol withdrawal

“…Since there was no placebo group included, it would be di¦cult directly to evaluate the expected incidence of seizures in this population and deduce that either drug was beneÞcial in inhibiting the occurrence of seizures. It should be noted, however, that extensive data document the anticonvulsant e¤ect of abecarnil in animals with chemically induced (Ozawa et al 1994b), electrically kindled Loscher et al 1991), and alcoholwithdrawal-induced (Crabbe 1992) convulsions.…”

“…Both animal (Ozawa et al 1994a) and human (Duka et al 1993) studies have indicated that abecarnil has fewer sedative properties than classical benzodiazepines, like diazepam. A di¤erential rate of treatment emergent drowsiness between the two medication groups was not observed in this alcohol withdrawal study, even though about 30 40 % of all individuals complained of this at some time during their participation.…”

“…When compared with benzodiazepines, abecarnil interacted less with alcohol ) and produced minimal or no tolerance (Serra et al 1994) or physical dependence (Steppuhn et al 1993). In addition, abecarnil exhibited anticonvulsant properties Loscher et al 1991), without the development of tolerance to this e¤ect that was observed in diazepam-treated animals (Ozawa et al 1994b).…”

“…One such agent is the beta-carboline, abecarnil, which has a high a¦nity for benzodiazepine receptors but which acts pharmacologically like a partial agonist ). For instance, in rodents and monkeys abecarnil exhibited anxiolytic e¤ects while showing little of the sedative or ataxic e¤ects caused by benzodiazepines (Ozawa et al 1994a). While ataxia was not found in animals, it did occur in human studies, but very little sedation in humans was reported (Duka et al 1993).…”