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 a GABAA receptor-based anxioselective resulted in multiple compounds entering clinical trials. 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 Alpidem was briefly marketed for the treatment of anxiety, but withdrawn because of liver toxicity.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 GABAA receptor-based anxioselectives. However, despite the formidable molecular toolbox at our disposal, we are no better informed about the GABAA receptors responsible for an anxioselective profile in the clinic. Here, I discuss the evolution of a quest, spanning 4 decades, for molecules that retain the rapid and robust anti-anxiety actions of benzodiazepines absent the side effects that limit their usefulness.

Restoring the Spinal Pain Gate

“…Moreover, biochemical experiments suggest that the H/R point mutation in the α subunit not only abolishes modulation by diazepam but also impairs the interaction with the γ subunit. This may eventually lead to false negative results in experiments with H/R point-mutated mice and may contribute to some of the discrepancies between predictions made from the H/R point-mutated mice and results obtained with subtype-selective agents (Sigel & Steinmann, 2012;Skolnick, 2012). Experiments comparing the phenotypes of single point-mutated mice and of triple point-mutated mice in which only a single subtype remains benzodiazepine-sensitive may provide additional insights also here.…”

A novel GABAA alpha 5 receptor inhibitor with therapeutic potential

“…Indeed, by systematic analysis of the effects of diazepam in strains of mice in which one of the 4 diazepam sensitive genes (1-3, 5) was rendered unresponsive to the drug, (Low et al, 2000;McKernan et al, 2000) it was possible to dissect the relative contributions of GABA A receptor isoforms to the pharmacologic profile of diazepam (Rudolph and Möhler, 2014). Thus, the case for producing isoform-selective GABA Aergic drugs devoid of unwanted side-effects such as sedation, pharmaco-dependence, muscle weakness, ataxia, and amnesia in the case of agonists, anxiety, convulsions and insomnia in the case of inhibitors had a sound scientific rationale (Atack, 2011;Skolnick, 2012). However, more than two decades of effort to produce selective and clinically viable BDZ-site ligands has yielded a single compound, RG1662 (Knust et al, 2009) that is still in clinical trials, while all others have failed.…”

“…However, more than two decades of effort to produce selective and clinically viable BDZ-site ligands has yielded a single compound, RG1662 (Knust et al, 2009) that is still in clinical trials, while all others have failed. The reasons for failure were diverse and have been reviewed extensively (Atack, 2010(Atack, , 2011Skolnick, 2012). receptors ( Fig.…”

2-Phenylimidazo[1,2-a]pyridine-containing ligands of the 18-kDa translocator protein (TSPO) behave as agonists and antagonists of steroidogenesis in a mouse leydig tumor cell line

“…alpidem; Langer et al, 1990). The TSPO ligand alpidem has attracted interest as it exhibits an anxioselective anxiolytic pharmacological profile sans benzodiazepine-like sedative side effects in preclinical animal models and clinically in humans; alpidem has been withdrawn from human use, however, owing to hepatoxicity (Skolnick, 2012). Alpidem has been shown to act on both TSPO and the central benzodiazepine receptor (CBR), with a preference toward TSPO.…”