Review
Anxioselective anxiolytics: can less be more?

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Abstract

Benzodiazepines remain widely used for the treatment of anxiety disorders despite a side-effect profile that includes sedation, myorelaxation, amnesia, and ataxia, and the potential for abuse. γ-Aminobutyric acidA (GABAA) receptor partial agonists, subtype-selective agents, and compounds combining both of these features are being developed in an attempt to achieve benzodiazepine-like efficacy without these potentially limiting side effects. This article reviews the nonclinical and clinical studies of “anxioselective” anxiolytics that target GABAA receptors and discusses potential mechanisms subserving an anxioselective profile.

Introduction

Anxiety is broadly defined as a state of unwarranted or inappropriate worry, often accompanied by restlessness, tension, distraction, irritability, and sleep disturbances. This disproportionate response to environmental stimuli can hyperactivate the hypothalamic–pituitary–adrenal axis and the autonomic nervous system, resulting in the somatic manifestations of anxiety, including shortness of breath, sweating, nausea, rapid heartbeat, and elevated blood pressure (Sandford et al., 2000). The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (2000) has classified anxiety disorders into multiple distinct conditions, including generalized anxiety disorder, acute stress disorder, obsessive–compulsive disorder, panic disorder, posttraumatic stress disorder, social and other specific phobias alone or in combination with the above disorders, as well as substance-induced anxiety disorders. Generalized anxiety disorder is the most common of the anxiety disorders, with a lifetime prevalence of approximately 5% (Wittchen and Hoyer, 2001). Every year, it is estimated that approximately 15 million people in the United States suffer solely from an anxiety disorder, with an additional 11 million suffering from anxiety as a comorbidity with at least one other psychiatric disorder (Greenberg et al., 1999). Moreover, anxiety has a lifetime prevalence of 1.5–3.5% of the population of the United States (Greenberg et al., 1999, Rice and Miller, 1998). Taken together, the total cost of anxiety disorders in the United States was estimated to be in excess of US$42 billion in 1990 (Greenberg et al., 1999, Rice and Miller, 1998). Therefore, anxiety disorders represent not only a significant public health issue, but place a substantial economic burden on society.

A number of novel compounds have either been developed or are currently in development for treating the different subclasses of anxiety. Some of these agents, such as the tricyclic antidepressants and β-adrenoceptor antagonists, found either limited use in treating specific disorders such as performance anxiety (e.g., β-adrenoceptor antagonist suppression of the sympathetic manifestations of anxiety), or have fallen out of favor for reasons of efficacy and/or safety. Currently, direct and indirect serotonin receptor agonists [e.g., serotonin-selective reuptake inhibitors (SSRIs) and buspirone] and benzodiazepines are most often prescribed for treating anxiety disorders, with the benzodiazepine receptor agonists remaining the preferred therapeutic modality (Atack, 2003, Stahl, 2002, Uhlenhuth et al., 1999, Varia and Rauscher, 2002). The ability of the benzodiazepines to enhance γ-aminobutyric acid (GABA) neurotransmission safely and rapidly is central to their effectiveness in treating anxiety disorders, especially generalized anxiety disorder and panic disorder (Stahl, 2002). Nonetheless, the use of benzodiazepines is limited by side effects associated with enhanced GABAergic neurotransmission, manifesting as sedation, muscle relaxation, amnesia, and ataxia. Moreover, a potential for abuse and dependence is associated with the long-term use of benzodiazepines. These therapeutic limitations and the societal burdens of anxiety provide the impetus for the development of new, anxioselective agents.

The concept of anxioselectivity is used here to describe anxiolysis in the absence of the side effects typically associated with benzodiazepines. While the historical target for anxioselective agents has been, and remains, the γ-aminobutyric acidA (GABAA) receptors (Atack, 2003, Lippa et al., 1979b, Lippa et al., 1982), other molecular loci have also been targeted, including metabotropic glutamate receptors (Schoepp et al., 1999), receptors for neurokinins and other peptides (Griebel, 1999, Millan et al., 2001), and serotonergic neurotransmission (Gorman and Kent, 1999, Riblet et al., 1982). However, none of these alternative targets has been shown to match either the efficacy or rapid onset of the benzodiazepines. This review will focus on the GABAergic mechanisms involved in achieving anxioselectivity, and summarize the current status of putative anxioselective agents.

Section snippets

GABAergic neurotransmission

GABA is the predominant inhibitory neurotransmitter in the central nervous system (CNS), with 30% of all synapses classified as GABAergic. The intrinsic inhibitory signal of GABA is transduced by a family of synaptic and extrasynaptic hetero-oligomeric proteins referred to as the GABAA receptors (Barnard et al., 1998, Korpi et al., 2002a, Korpi et al., 2002b). When GABA binds to its recognition site, the receptor complex is activated, causing a Cl-permeant anion channel to open, allowing Cl

Molecular genetic evidence of anxioselectivity

Important insights into the behaviors resulting from activation of GABAA receptors containing defined α subunits have been provided by investigations using transgenic mice, and in particular those with “knock-ins” of an α subunit with point mutations rendering the GABAA receptor insensitive to modulation by benzodiazepines. This is accomplished by replacing a histidine residue in the benzodiazepine binding region (residue 101 in the α1 and α2 subunits, residue 126 in the α3 subunit, and residue

Pharmacological evidence of anxioselectivity

The above investigations suggest that the sedative and anxiolytic properties of benzodiazepine agonists can be differentiated and may be mediated through specific GABAA receptors. Nonetheless, the data obtained from studies of knock-in mice remain difficult to reconcile with data obtained from pharmacological investigations. 6-(3-Pyridyl)-5-(4-methoxyphenyl)-3-carbomethoxy-1-methyl-1H-pyridin-2-one was found to be a high-affinity inverse agonist at the GABAA3a receptor (Collins et al., 2002).

Bretazenil

Bretazenil is an imidazobenzodiazepine that does not exhibit GABAA receptor subtype selectivity in vitro (Griebel, 1999, Haefely, 1984, Martin et al., 1988). Biochemical and electrophysiological assays in vitro indicate that bretazenil is a partial agonist, with a maximal degree of cGMP inhibition of 25–50% in rodent cerebellum (compared to 75% for diazepam; Martin et al., 1988). GABA-gated Cl currents in recombinant GABAA receptors containing α3 or α5 subunits were enhanced to a maximum of

L-838417

L-838417 is a pyridone with a unique efficacy profile. Radioligand binding assays indicate that it has uniformly high affinity among the diazepam-sensitive GABAA receptors (McKernan et al., 2000). However, not only is it a partial agonist at α2, α3, and α5 subunit-containing constructs compared to diazepam (Emax 39–43%), but it is GABA-neutral at α1 subunit-containing constructs as determined by modulation of GABA-gated Cl currents in recombinantly expressed GABAA receptors. Tests in vivo

Conclusion

The benzodiazepines were the first truly safe and effective anxiolytics, and remain a mainstay of both general and psychiatric practice because of their rapid and efficacious action. However, issues related to their sedation, ataxia, and abuse potential have led to the increasing use of SSRIs (despite their slow onset and marginal efficacy) for the treatment of generalized anxiety disorder. This review describes several of the approaches that have evolved to develop anxioselective agents acting

Acknowledgements

We thank Dr. J. Atack for permitting us to cite his unpublished data.

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