title: Anxioselective anxiolytics: on a quest for the Holy Grail.
abstract: The discovery of benzodiazepine receptors provided the impetus to discover and develop anxioselective anxiolytics ('Valium without the side effects'). The market potential for an anxioselective based on the γ-aminobutyric acid A (GABA(A)) receptor resulted in clinical trials of multiple compounds. In contrast to the anxioselective profile displayed in preclinical models, compounds such as bretazenil, TPA023, and MRK 409 produced benzodiazepine-like side effects (sedation, dizziness) in Phase I studies, whereas alpidem and ocinaplon exhibited many of the characteristics of an anxioselective in the clinic. Alpidem was briefly marketed for the treatment of anxiety, but was withdrawn because of liver toxicity. Reversible elevations in liver enzymes halted development of ocinaplon in Phase III. The clinical profiles of these two molecules demonstrate that it is possible to develop GABA(A) receptor-based anxioselectives. However, despite the formidable molecular toolbox at our disposal, we are no better informed about the GABA(A) receptors responsible for an anxioselective profile in the clinic. Here, I discuss the evolution of a quest, spanning four decades, for molecules that retain the rapid and robust anti-anxiety actions of benzodiazepines without the side effects that limit their usefulness.
authors.affiliation: Division of Pharmacotherapies and Medical Consequences of Drug Abuse, National Institute on Drug Abuse, National Institutes of Health, 6001 Executive Boulevard, Suite 4123, Bethesda, MD 20892, USA. phil.skolnick@nih.gov
authors.forename: Phil
authors.initials: P
authors.lastname: Skolnick
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001008:Anxiety Disorders / Q000188:drug therapy* / Q000378:metabolism; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D006801:Humans; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A