Karin Gabriele Steppuhn

Abecarnil: A Novel Anxiolytic with Mixed Full Agonist/Partial Agonist Properties in Animal Models of Anxiety and Sedation

Although the benzodiazepines are without doubt the most effective agents currently available for the treatment of anxiety disorders, they possess a number of properties which limit their use or which give rise to problems on withdrawal. Thus, currently available benzodiazepine anxiolytics are sedative and muscle relaxant, induce memory impairment, increase the intoxicating potency of alcohol, may be subject to nontherapeutic use (abuse), and, following chronic use, may give rise to problems of dependence. For these reasons, it has been the aim of medicinal chemistry to synthesize compounds with the therapeutic strengths of the benzodiazepines, but avoiding their unwanted properties. Given the proven efficacy of anxiolytics acting at benzodiazepine receptors, an obvious approach is to seek compounds acting at this site, but which have been modified so that the unwanted properties of the benzodiazepines have been eliminated. In recent years, two approaches have been used to achieve a better dissociation of the effects of benzodiazepine-receptor ligands; the first entails the use of compounds acting at partial agonists at benzodiazepine receptors (Haefely et al. 1990), but with the discovery of a number of subtypes of y-amino- butyric acid type A (GABAA) receptors, a second approach has become feasible. Although pharmacological evidence for benzodiazepine-receptor heterogeneity has existed for some time (Corda et al. 1988; Squires et al. 1979), it is only recently that the application of molecular biological techniques to the understanding of GABAA receptors has allowed us a fuller understanding of their complexity (see Luddens, this volume).