Nonsedating anxiolytics.

Anxiety disorders are the most prevalent psychiatric pathology with substantial cost to society, but the existing treatments are often inadequate. This has rekindled the interest in the GABA-receptor (GABAR) positive allosteric modulator (PAM) compounds, which have a long history in treatment of anxiety beginning with diazepam, chlordiazepoxide, and alprazolam. While the GABAR PAMs possess remarkable anxiolytic efficacy, they have fallen out of favor due to a host of adverse effects including sedation, motor impairment, addictive potential and tolerance development. A substantial effort was thus devoted to the design of GABAR PAMs as anxiolytics with reduced sedative liabilities. Several non-benzodiazepine (BZD) GABAPAMs progressed to clinical trials (bretazenil, abecarnil, alpidem, and ocinaplon) with alpidem obtaining regulatory approval as anxiolytic, but later withdrawn from market due to hepatotoxicity. Advances in molecular biology gave birth to a host of subtype selective GABAR-PAMs which suffered from signs of sedation and motor impairment and only three compounds progressed to proof-of-concept studies (TPA-023, AZD7325 and PF-06372865). TPA-023 was terminated due to toxicity in preclinical species while AZD7325 and PF-06372865 did not achieve efficacy endpoints in patients. We highlight a new compound, KRM-II-81, that is an imidazodiazepine selective for GABAR containing α2/3 and β3 proteins. In preclinical studies KRM-II-81 produced anxiolytic-like effects but with minimal sedation, respiratory depression, and abuse liability. Thus, KRM-II-81 is a newly discovered, non- BZD anxiolytic compound, which targets a selective population of GABAR for improved therapeutic gain and reduced side effects.