GABA-A receptors: a viable target for novel anxiolytics?

https://doi.org/10.1016/j.coph.2005.08.005Get rights and content

Benzodiazepine (BZ) anxiolytics mediate their clinical effects by enhancing the effect of γ-aminobutyric acid (GABA) at the GABA-A receptor. Classical BZ full agonists such as diazepam, which maximally enhance the function of GABA-A receptors, are effective anxiolytics but carry unwanted side effects including sedation, dependence and abuse liability, limiting their utility. Although a second generation of ’partial agonist’ BZs have been pursued, promising preclinical data, in terms of anxiolytic efficacy and decreased unwanted effects, have so far failed to translate to the clinic. Following the insights into GABA-A receptor subtypes mediating the effects of BZs, a third generation of ’receptor subtype-selective’ BZ site ligands have been developed. However, it remains to be determined whether promising preclinical data are recapitulated in the clinic.

Introduction

Anxiety disorders are a prevalent and disabling set of diseases which continue to represent a significant disease burden [1]. They can be categorized further into several distinct subgroups, including generalised anxiety disorder (the largest group), panic disorder, social anxiety and various phobias. For about 30 years from the 1960s, the gold standard treatment of anxiety disorders were the benzodiazepines (BZs), exemplified by drugs such as Valium (diazepam) from Hoffmann la Roche. BZs had an improved safety profile over the barbiturate drugs that they largely replaced, and had a rapid onset of efficacy much valued by the patient. However, BZs were not perfect drugs [2], and their sedative properties, cognitive impairing effects and, perhaps most importantly of all, dependence and abuse liability has generated a significant negative perception in the eyes of the regulatory agencies, prescribing clinicians and the general public. As such, in recent years, anxiety disorders have frequently been treated with the antidepressant selective serotonin reuptake inhibitors (SSRIs) [3]. This is in large part because the SSRIs lack the side effects that beset the BZs, and also because anxiety is often comorbid with depressive disorders. The major disadvantage of SSRIs is their speed of onset of efficacy. This is generally of the order of several weeks, and is undoubtedly an important disadvantage in treating the symptoms of anxiety. Thus, an unmet medical need and market opportunity exists if an anxiolytic could be developed which has a rapid onset of action but lacks the unwanted effects of existing BZs. The evolving science and our understanding of the diversity of the GABA-A receptor family might represent a path forward to such a goal.

Section snippets

GABA-A receptors

γ-aminobutyric (GABA) is the major inhibitory neurotransmitter in the mammalian brain [4] and its effects are mediated through two types of receptors, the ionotropic GABA-A and the metabotropic GABA-B (as discussed in other reviews in this issue). The GABA-A receptor is a member of the ligand-gated ion channel superfamily exemplified by the nicotinic acetylcholine receptor [5]. Its activation by GABA opens the intrinsic ion channel, enabling flux of chloride through the channel into the cell,

BZ site partial agonists as anxiolytics

Around 15 years ago, the concept emerged that a BZ with lower efficacy at the GABA-A receptor than the classical full agonist BZs might maintain the beneficial anxiolytic properties but have a lower propensity to cause the unwanted side effects discussed above. In preclinical animal assays, it did indeed appear that compounds with this profile retained their anxiolytic activity but had decreased sedation, withdrawal and abuse liability. Examples of such compounds are bretazenil [16] and

GABA-A receptor subtype-selective anxiolytics

There are two approaches to developing a receptor subtype-selective modulator (Figure 1). The most obvious approach is to develop a compound with binding selectivity — that is, with higher affinity for one receptor subtype than for another. For GABA-A receptors, the clear example is zolpidem, which, as discussed above, has higher affinity for α1 subunit-containing receptors. The alternative approach is to develop compounds with efficacy selectivity — that is, compounds which might bind with

Conclusions

An important unmet medical need, and a significant commercial opportunity, exists for a novel, fast-acting anxiolytic agent lacking the unwanted side effects of classical, full agonist, nonselective BZs. To date, the ‘second generation’ partial agonist approach has not achieved this goal, with encouraging preclinical data failing to translate into a clear clinical advantage; however, ocinaplon might paradoxically prove to be the exception, although further clinical data are required. A more

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

References (31)

  • C.J. Rogers et al.

    Benzodiazepine and beta-carboline regulation of single GABAA receptor channels of mouse spinal neurones in culture

    J Physiol

    (1994)
  • E.R. Korpi et al.

    GABA(A)-receptor subtypes: clinical efficacy and selectivity of benzodiazepine site ligands

    Ann Med

    (1997)
  • R.M. McKernan et al.

    Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype

    Nat Neurosci

    (2000)
  • U. Rudolph et al.

    Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes

    Nature

    (1999)
  • K. Low et al.

    Molecular and neuronal substrate for the selective attenuation of anxiety

    Science

    (2000)
  • Cited by (119)

    View all citing articles on Scopus
    View full text