Abstract
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 Lüddens, this volume).
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
Similar content being viewed by others
References
Boissier JR, Tardy T, Diverres JC (1960) Une novelle methode simple pour explorer taction “tranquillisante”: le test de la cheminee. Med Exp 3:81–84
Boissier JR, Simon P, Aron C (1969) A new method for the rapid screening of minor tranquillisers in mice. Eur J Pharmacol 4:142–150
Corda MG, Giorgi O, Longoni B, Ongini E, Montaldo S, Biggio G (1988) Preferential affinity of 3H-2-oxoquazepam for type I benzodiazepine recognition sites in the human brain. Life Sci 42:189–197
Crabbe J (1992) Antagonism of ethanol withdrawal convulsions in Withdrawal Seizure Prone mice by diazepam and abecarnil. Eur J Pharmacol 221:85–90
Haefely W, Martin JR, Schoch P (1990) Novel anxiolytics that act as partial agonists at benzodiazepine receptors. Trends Pharmacol Sci 11:452–456
Jones GH, Schneider HH, Schneider C, Stephens DN (1993) Comparison of abecarnil with other benzodiazepine-receptor ligands in two models of anxiolytic activity in the mouse: an analysis based on fractional receptor occupancies. Psychopharmacology (in press)
Knoflach F, Drescher U, Scheurer L, Malherbe P, Möhler H (1993) Full and partial agonism displayed by benzodiazepine-receptor ligands at different recombinant GABAA-receptor subtypes. Mol Pharmacol (in press)
Löscher W, Hönack D (1992) Withdrawal precipitation by benzodiazepine-receptor antagonists in dogs chronically treated with diazepam or the novel anxiolytic and anticonvulsant ß-carboline abecarnil. Naunyn Schmiederbergs Arch Pharmacol 345:452–460
Löscher W, Hönack D, Scherkl R, Hashem A, Frey H-H (1990) Pharmacokinetics, anticonvulsant efficacy and adverse effects of the ß-carboline, abecarnil, a novel ligand for benzodiazepine receptors, after acute and chronic administration in dogs. J Pharmacol Exp Ther 255:541–548
Nielsen M, Braestrip C (1980) Ethyl ß-carboline-3-carboxylate shows differential benzodiazepine-receptor interaction. Nature 286:606–607
Petersen EN, Jensen LH, Honore T, Braestrup C, Kehr W, Stephens DN, Wachtel H, Seidelman D, Schmiechen R (1984) ZK 91296, a partial agonist at benzodiazepine receptors. Psychopharmacology 83:240–248
Pitterman W, Sontag K-H, Wand P, Rapp K, Deerberg F (1976) Spontaneous occurrence of spastic paresis in Han-Wistar rats Neurosci Lett 2:45–49
Poitier MC, Prado de Carvalho L, Dodd RH, Besselievre R, Rossier J (1988) In vivo binding of ß-carbolines in mice: regional differences and correlation of occupancy to pharmacological effects. Mol Pharmacol 34:124–128
Pritchett DB, Lüddens H, Seeburg PH (1989) Type I and Type II GABAA-benzodiazepine receptors produced in transfected cells. Science 245:1389–1392
Squires RF, Benson DI, Braestrup C, Coupet J, Klepner CA, Myers V, Beer B (1979) Some properties of brain-specific benzodiazepine receptors: new evidence for multiple receptors. Pharmacol Biochem Behav 10:825–830
Stephens DN, Schneider HH, Kehr W, Jensen LH, Petersen EN, Honore T (1987) Modulation of anxiety by ß-carbolines and other benzodiazepine-receptor ligands: relationship of pharmacological to biochemical measures of efficacy. Brain Res Bull 19:309–318
Stephens DN, Schneider HH, Kehr W, Andrews JS, Rettig K-J, Turski L, Schmiechen R, Turner JD, Jensen LH, Petersen EN, Honore T, Bondo Hansen J (1990) Abecarnil, a metabolically stable, anxioselective ß-carboline acting at benzodiazepine receptors. J Pharmacol Exp Ther 253:334–343
Stephens DN, Turski L, Hillman M, Turner JD, Schneider HH, Yamaguchi M (1992) What are the differences between abecarnil and conventional benzodiazepine anxiolytics? In: Biggio G, Concas A, Costa E (eds) GABAergic synaptic transmission. Raven, New York, pp 395–405
Steppuhn K, Schneider HH, Turski L, Stephens DN (1993) Long-term treatment with abecarnil does not lead to dependence in mice. J Pharmacol Exp Ther 264:1395–1400
Turski L, Stephens DN, Jensen LH, Petersen EN, Meldrum BS, Patel S, Bondo Hansen J, Löscher W, Schneider HH, Schmiechen R (1990) Anticonvulsant action of the ß- carboline, abecarnil: studies in rodents and baboon, Papio papio. J Pharmacol Exp Ther 253:344–352
Turski L, Stephens DN (1993) Effects of the ß-carboline, abecarnil, on spinal reflexes in mice, and on muscle tone in genetically spastic rats: a comparison with diazepam. J Pharmacol Exp Ther (in press)
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1993 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Stephens, D.N., Turski, L., Jones, G.H., Steppuhn, K.G., Schneider, H.H. (1993). Abecarnil: A Novel Anxiolytic with Mixed Full Agonist/Partial Agonist Properties in Animal Models of Anxiety and Sedation. In: Stephens, D.N. (eds) Anxiolytic β-Carbolines. Psychopharmacology Series, vol 11. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-78451-4_7
Download citation
DOI: https://doi.org/10.1007/978-3-642-78451-4_7
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-78453-8
Online ISBN: 978-3-642-78451-4
eBook Packages: Springer Book Archive