Abecarnil Shows Reduced Tolerance Development and Dependence Potential in Comparison to Diazepam: Animal Studies

Abstract

Development of tolerance and dependence limits the therapeutic use of traditional benzodiazepine-(BZ) receptor agonists, such as diazepam (Owen and Tyrer 1983; Woods et al. 1987; Haefely et al. 1990). Recent reports have indicated that partial (low efficacy) BZ-receptor agonists, i. e., compounds which induce smaller fractional responses in their target cells than do full agonists at the same fractional receptor occupancy, may have advantages in this respect, because low-efficacy agonism prevents overstimulation of a receptor population, thereby reducing overdose problems, desensitization responses, and adaptation (Haigh and Feely 1988; Haefely et al. 1990). Indeed, repeated treatment of mice with the partial BZ-receptor agonist, bretazenil (Ro 16–6028), produced no significant tolerance to the anticonvulsant effect, in contrast to the effect of full agonists (Haigh and Feely 1988). Furthermore, again unlike full agonists, physical dependence could not be induced in squirrel monkeys after repeated very high doses of bretazenil as assessed by challenge with the BZ-receptor antagonist, flumazenil (Haefely et al. 1990). Although these data on bretazenil indicate that partial BZ-receptor agonism might have important practical consequences, there are also studies on other partial BZ-receptor agonists reporting less favorable data.