ReviewAnxioselective anxiolytics: can less be more?
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.
References (96)
- et al.
Pharmacology of recombinant gamma-aminobutyric acidA receptors rendered diazepam-insensitive by point-mutated alpha-subunits
FEBS Lett.
(1998) - et al.
Pharmacological profile of benzodiazepine site ligands with recombinant GABAA receptor subtypes
Eur. Neuropsychopharmacol.
(1996) Is there a future for neuropeptide receptor ligands in the treatment of anxiety disorders?
Pharmacol. Ther.
(1999)- et al.
Normal electrophysiological and behavioral responses to ethanol in mice lacking the long splice variant of the γ2 subunit of the γ-aminobutyrate type A receptor
Neuropharmacology
(1999) - et al.
Drug interactions at GABAA receptors
Prog. Neurobiol.
(2002) - et al.
Altered receptor subtypes in the forebrain of GABAA receptor delta subunit-deficient mice: recruitment of gamma 2 subunits
Neuroscience
(2002) - et al.
GABAA receptor alpha-1 subunit deletion alters receptor subtype assembly, pharmacological and behavioral responses to benzodiazepines and zolpidem
Neuropharmacology
(2002) - et al.
Alcohol modulation of cloned GABAA receptor–channel complex expressed in human kidney cell lines
Brain Res.
(1993) - et al.
A synthetic non-benzodiazepine ligand for benzodiazepine receptors: a probe for investigating neuronal substrates of anxiety
Pharmacol. Biochem. Behav.
(1979) - et al.
Molecular substrates of anxiety: clues from the heterogeneity of benzodiazepine receptors
Life Sci.
(1982)
Subtype-selective GABAergic drugs facilitate extinction of mouse operant behavior
Neuropharmacology
Which GABAA-receptor subtypes really occur in the brain?
Trends Neurosci.
Anxiolytic properties of the selective, non-peptidergic CRF(1) antagonists, CP154,526 and DMP695: a comparison to other classes of anxiolytic agent
Neuropsychopharmacology
GABAA receptor subtypes: dissecting their pharmacological functions
Trends Pharmacol. Sci.
The psychobiology of anxiolytic drugs: Part 1. Basic neurobiology
Pharmacol. Ther.
Pharmacological agents acting at subtypes of metabotropic glutamate receptors
Neuropharmacology
β-Carboline-3-carboxylate-t-butyl ester: a selective BZ1 benzodiazepine receptor antagonist
Life Sci.
Some properties of brain specific benzodiazepine receptors: new evidence for multiple receptors
Pharmacol. Biochem. Behav.
Ethanol potentiation of GABAA receptors requires phosphorylation of the alternatively spliced variant of the γ2 subunit
FEBS Lett.
A single histidine in GABAA receptors is essential for benzodiazepine agonist binding
J. Biol. Chem.
Pharmacological profile of the imidazopyridine zolpidem at benzodiazepine receptors and electrocorticogram in rats
Naunyn-Schmiedeberg's Arch. Pharmacol.
Anxioselective compounds acting at the GABAA receptor benzodiazepine binding site
Curr. Drug Targets. CNS Neurol. Disord.
The first double-blind, placebo-controlled trial of a partial benzodiazepine agonist abecarnil (ZK 112–119) in generalized anxiety disorder
Psychopharmacol. Bull.
International Union of Pharmacology: XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function
Pharmacol. Rev.
Efficacy of ocinaplon, a novel GABAA receptor modulator, in generalized anxiety
Abstr.-Soc. Neurosci.
Beta-CCT, a selective BZ-omega1 receptor antagonist, blocks the anti-anxiety but not the amnesic action of chlordiazepoxide in mice
Behav. Pharmacol.
Identification of a novel, selective GABAA alpha 5 receptor inverse agonist which enhances cognition
J. Med. Chem.
Ocinaplon
Drugs Future
3-Heteroaryl-2-pyridones: benzodiazepine site ligands with functional selectivity for alpha 2/alpha 3-subtypes of human GABAA receptor-ion channels
J. Med. Chem.
Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the α5 subunit of the GABAA receptor
J. Neurosci.
BZ1 receptor subtype specific ligands. Synthesis and biological properties of BCCt, a BZ1 receptor subtype specific antagonist
Med. Chem. Res.
Decreased GABAA receptor clustering results in enhanced anxiety and a bias for threat cues
Nat. Neurosci.
Mechanism of action of the hypnotic zolpidem in vivo
Br. J. Pharmacol.
Molecular targets for the myorelaxant action of diazepam
Mol. Pharmacol.
Trace fear conditioning involves hippocampal alpha 5 GABAA receptors
Proc. Natl. Acad. Sci. U. S. A.
A double-blind, placebo controlled study of DOV 273,547 (Ocinaplon) in the treatment of generalized anxiety disorder (GAD)
Abstr.-Soc. Neurosci.
Ocinaplon: a new anxio-selective agent in patients with GAD
Am. Psychiatr. Assoc.
Zaleplon displays a selectivity to recombinant GABAA receptors different from zolpidem, zopiclone and benzodiazepines
Neurosci. Res. Commun.
Pharmacotherapy of generalized anxiety disorder
J. Clin. Psychiatry
5-Ethoxymethyl-7-fluoro-3-oxo-1,2,3,5-tetrahydrobenzo[4,5]imidazo[1,2a]pyridine-4-N-γ2-fluorophenyl)carboxamide (RWJ-51204), a new nonbenzodiazepine anxiolytic
J. Pharmacol. Exp. Ther.
Human studies on abecarnil a new beta-carboline anxiolytic: safety, tolerability and preliminary pharmacological profile
Br. J. Clin. Pharmacol.
Relationship between benzodiazepine receptor occupancy and functional effects in vivo of four ligands of differing intrinsic efficacies
J. Pharmacol. Exp. Ther.
SSRIs and SMRIs: broad spectrum of efficacy beyond major depression
J. Clin. Psychiatry
The economic burden of anxiety disorders in the 1990s
J. Clin. Psychiatry
New evidence that the pharmacological effects of benzodiazepine receptor ligands can be associated with activities at different BZ (omega) receptor subtypes
Psychopharmacology (Berl.)
Comparison of the pharmacological properties of classical and novel BZ-omega receptor ligands
Behav. Pharmacol.
SL-651498, a GABAA receptor agonist with subtype-selective efficacy, as a potential treatment for generalized anxiety disorder and muscle spasms
CNS Drug Rev.
Pharmacological profile of two benzodiazepine partial agonists: Ro 16-6028 and Ro 17-1812
Clin. Neuropharmacol.
Cited by (53)
Neuropharmacological potentials of β-carboline alkaloids for neuropsychiatric disorders
2021, European Journal of PharmacologyEffects of a hydroethanolic extract of Boophone disticha bulb on anxiety-related behaviour in naive BALB/c mice
2018, Journal of EthnopharmacologyCitation Excerpt :Clinical signs of this side effect include, ataxia, amnesia, muscle relaxation and sedation. Furthermore, there exists a potential for abuse and dependence associated with long-term use of these medicines (Basile et al., 2004; Cryan and Sweeney, 2011). Antidepressants like selective serotonin reuptake inhibitors (SSRI) and tricyclic acids (TCAs) are used to treat anxiety disorder, yet, they also produce many systemic side effects associated with their chronic use (Cryan and Sweeney, 2011).
Characterization of GABA<inf>A</inf> receptor ligands with automated patch-clamp using human neurons derived from pluripotent stem cells
2016, Journal of Pharmacological and Toxicological MethodsCitation Excerpt :The most abundant GABAAR is α1β2γ2, with only a few brain regions lacking this receptor (Sieghart & Sperk, 2002). Benzodiazepines have been hailed as prototypic antianxiety agents, and although there are many alternatives to treating anxiety, none have matched the high efficacy and the rapid onset of these drugs (Basile, Lippa, & Skolnick, 2004). Furthermore, more than 50 years of clinical experience has demonstrated their extremely low degree of toxicity.
Anxiolytics
2012, Handbook of Clinical NeurologyHomology modeling and atomic level binding study of GABA<inf>A</inf> receptor with novel enaminone amides
2010, European Journal of Medicinal ChemistryCitation Excerpt :To more fully probe the interactions of this novel enaminone amides with GABAAR, 12 ligands were docked into the putative binding pocket of rat α1β2γ2 GABARs. These ligands from Hogenkamp’s Lab have the same skeleton structure, which is 2-(2-chlorobenzoyl)-3-(4-chlorophenylamino)acrylamide [18]. The different substitutional groups conferred these compounds to the diverse activity.