- 1 Novel Anxiolytics Acting At Benzodiazepine Receptors
- 2 Neurosteroids
- 3 Drugs Acting On Serotonin Receptors
- 4 Drugs Acting On Neuropeptide Receptors
- 5 Excitatory Amino Acid Receptors
- 6 Overview of New Anxiolytics: Conclusion
- 7 Related Posts
Although the benzodiazepines have been the treatment of choice for anxiety disorders for many years, unfavorable aspects to their side-effect profile have initiated efforts to develop new-generation antianxiety agents. Over the past decade, scientists have been searching for compounds that retain the robust anxiolytic efficacy of benzodiazepines, but lack a number of unwanted properties, including sedation, cognitive impairments such as memory disturbance, and drug dependence. Two major strategies for developing new anxiolytic agents have been used. The first is based on development of compounds that act as partial agonists at benzodiazepine receptors. The second is leading psychopharmacologists to focus on developing agents active at various other neurotransmitter receptors, including those for serotonin (5-hydroxytryptamine (5-HT)), cholecystokinin (CCK), neuropeptide Y; corticotropin-releasing factor (CRF), and glutamate. Because these various neurotransmitters are involved in the neurobiology of anxiety, compounds acting on these systems may be effective anxiolytics. Recent preclinical and clinical data, in fact, support the idea that selective ligands for 5-HT1A, 5-HT2A, 5-HT2C, 5-HT3, CCK-B, and N-methyl-D-aspartate (NMDA) subtype of glutamate receptors are of potential interest for the development of novel anxiolytics. In this chapter, we discuss research strategies based on both approaches and propose future directions for the development of new anxiolytics.
Novel Anxiolytics Acting At Benzodiazepine Receptors
The anxiolytic, sedative, hypnotic, and muscle relaxant properties of benzodiazepines result from benzodiazepine interaction with central nervous system benzodiazepine receptors. Receptors for benzodiazepines in the central nervous system are part of a supramolecular complex that also includes binding sites for γ-aminobutyric acid (GABA), barbiturates, picrotoxin, beta-carbolines, and an associated chloride ionophore that may be conceptualized as the effector of this receptor complex (). All of the binding sites within this supramolecular complex are allosterically interrelated in that binding at any one of these positions alters the binding kinetics at other subunits of this complex (). At least five benzodiazepine receptor subtypes have been identified. Diversity among various subtypes lies in the differences of their apparent sensitivity to GABA and in the structural and functional heterogeneity of the allosteric centers modulating the primary transmitter recognition site located on the supramolecular receptor complex (). Benzodiazepine 1, or omega 1, receptor subtype seems to mediate anxiolytic action of benzodiazepines.
The novel imidazopyridazines alpidem and zolpidem have high selectivity for benzodiazepine 1 sites yet seem to be less deleterious than classic benzodiazepines acting at benzodiazepine 1 and 2 sites, with regard to memory and learning capacity (). Alpidem is registered in Europe as an anxiolytic and is proven to be effective in the treatment of generalized anxiety disorder, stress-induced anxiety, and adjustment disorder with anxious mood (). Alpidem has a good safety profile, is well tolerated, and displays very low potential to induce dependence or to develop tolerance (). Zolpidem has been registered in the United States and Europe as a hypnotic agent and produces sedation without tolerance, dependence, or the withdrawal liability of sedative-hypnotic benzodiazepines ().
Abecarnil, a beta-carboline-3-carboxylic-ester, has a selective pharmacological profile in animal studies and is under development for the treatment of generalized anxiety disorder. It has anxiolytic and anticonvulsant activity, with a low abuse liability and low dependence potential (). Although the initial results of phase II clinical trials were promising (), they have not been yet confirmed in phase III clinical trials.
The promising anxiolytic-antipanic preclinical profile of bretazenil, an imidazobenzodiazepine congener of the benzodiazepine antagonist flumazenil (), also has not been confirmed in large-scale clinical testing.
Neurosteroids are natural or synthetic steroids that rapidly alter the excitability of neurons by interacting at benzodiazepine receptors (). Neurosteroid anxiolytics are still early in their development for application as possible anxiolytic agents. For example, allotetrahydro-deoxycorticosterone shows anxiolytic activity in animal models of anxiety (). This finding led to the suggestion that neurosteroids may represent an important class of new anxiolytic drugs with rapid onset of action (). The 3a-hydroxy ring A-reduced metabolites of progesterone, such as alfaxalone, allopregnanolone, and allotetrahydrodeoxycorticosterone, augment inhibitory neurotransmission through interaction with the GABAA-benzodiazepine-chloride channel receptor complex in the central nervous system and possess sedative-hypnotic action ().
Drugs Acting On Serotonin Receptors
Evidence from numerous preclinical and clinical studies suggests that dysfunction of serotonin neurons plays a role in the pathophysiology of anxiety. Since the early 1980s, the classic hypothesis of serotonin function in anxiety has suggested that the serotonin system promotes anxiety, whereas suppression of this system diminishes it. The discovery of numerous serotonin receptor subtypes has extended our understanding of the role of the serotonin system in anxiety and is extending the simple classic hypothesis of serotonin function into a far more complex story involving multiple specific subtypes of serotonin receptors. For example, current knowledge suggests that even increased serotonin activity can reduce anxious behavior under certain circumstances and at certain serotonin receptor subtypes ().
Researchers are currently attempting to develop new potential anxiolytic drugs by targeting various serotonin receptors selectively. Among 18 or more identified serotonin receptors subtypes, it seems that 5-HT1A, 5-HT2A, 5-HT2C, and 5-HT3 receptors may be especially involved in the serotonin system’s response in anxiety. Most interest has focused around 5-HT1A drugs (buspirone, ipsapirone, gepirone, tandospirone, flesinoxan, and others). Some preclinical data indicate that antagonists at 5-HT2A, 5-HT2C, and 5-HT3 receptors may also exert anxiolytic activity, but so far these findings have not been consistently confirmed in clinical trials.
Drugs Acting on 5-HT1A Receptors
Buspirone, a 5-HT1A partial agonist, is the first drug acting on serotonin receptors to be approved in the United States for the treatment of anxiety. Its clinical efficacy is equivalent to that of benzodiazepines in patients with generalized anxiety disorder, with evidently lower incidence of adverse reactions (). Moreover, buspirone produces no withdrawal symptoms or low-dose dependence (). However, the onset of anxiolytic effects is delayed compared with that of benzodiazepines (), and some clinicians doubt that buspirone has efficacy comparable to that of benzodiazepines. A possibility of buspirone augmentation of benzodiazepines’ activity has been suggested. Currently, several new compounds, such as ipsapirone and flesinoxan, acting on the 5-HT1A receptor, are under evaluation in phase II and III clinical testing.
Drugs Acting on 5-HT2A and 5-HT2C Receptors
m-Chlorophenylpiperazine (mCPP) induces anxiety in human volunteers and laboratory animals. This effect can be blocked by the nonselective 5-HT2A/5-HT2C receptor antagonists (). In addition, several nonselective 5-HT2A/5-HT2C antagonists have been observed to possess anxiolytic profiles in animal models of anxiety, whereas selective 5-HT2A receptor antagonists were found to have no effect (). These findings led to the hypothesis that selective 5-HT2C antagonists might be useful in the treatment of anxiety. However, no such compound is yet available.
Drugs Acting on 5-HT3 Receptors
The 5-HT3 receptor is the only receptor among monoamine receptors coupled directly to a cation channel; therefore, the drug actions at this receptor subtype may be more rapid than drug actions at other serotonin receptor subtypes. Recently, many selective 5-HT3 receptor antagonists including ondansetron, zacopride, tropisetron, granisetron, zatosetron, and nazasetron have been developed. The 5-HT3 antagonists exhibit anxiolytic effects in animal models of anxiety (). Preclinical data also indicate that 5-HT3 antagonists are not sedative, do not have addictive liability, generate no problems withdrawing from chronic treatment, and can be used following benzodiazepine withdrawal (). Ondansetron, a 5-HT3 antagonist, is under investigation as a potential treatment for generalized anxiety disorder, panic disorder, and social phobia ().
Drugs Acting On Neuropeptide Receptors
In the past decade, several major advances have been made with regard to understanding the functional role of peptides in anxiety, but without major breakthroughs in terms of showing a causal relation between a peptide and anxiety or the therapeutic utility of peptide drugs for the treatment of anxiety. The major achievement in recent years has been the development of second-generation peptide antagonists, which are small molecules of nonpeptide nature that pass the blood-brain barrier. Several neuropeptides have been implicated in the neurobiology of anxiety, including CCK, CRF, and neuropeptide Y, which are reviewed here.
A gastrinlike neuropeptide, CCK exists in the central nervous system both as an octapeptide (CCK-8) and as a tetrapeptide (CCK-4) (). The octapeptide CCK-8 occurs predominantly in sulfated form and is one of the most abundant neuropeptides in the central nervous system (). Two major subtypes of CCK receptors, labeled as CCK-A and CCK-B receptors, have been identified (). At this point, the most promising neuropeptide receptor to target for the treatment of anxiety may be the CCK-B receptor. This receptor is widely distributed throughout the brain, with particular distribution in limbic structures and cortical areas (). Agonists acting at CCK-B receptors have anxiogenic-like effects in various animal tests, whereas human studies have demonstrated panicogenic effects of the CCK-B agonist CCK-4 (). Recently developed CCK-B receptor antagonists, such as RB-211, CI-988, and L-365,260, have shown anxiolytic-like actions (), probably mediated through the dorsal vagal complex at the bulbar level rather than through limbic structures. The development of compounds that specifically antagonize CCK-B receptors may be of potential therapeutic activity in the treatment of anxiety disorders.
Evidence of the involvement of CCK-B receptors in the neurobiology of anxiety has been strengthened by the findings that a closely related peptide, pentagastrin, produces dose-related and time-limited symptoms of social anxiety in both control subjects and patients with social phobia undergoing experimental social interactions (). Pentagastrin is a pentapeptide whose final tetrapeptide is identical to CCK-4.
An interesting link appears to exist in the brain between CCK and 5-HT3 receptors. Activation of 5-HT3 receptors increases CCK release from rat cortical and nucleus accumbens synaptosomes (), suggesting that anxiolytic activity of 5-HT3 antagonists may be mediated through blockade of the CCK system.
Preclinical data demonstrate that CRF administration produces several behavioral effects characteristic of anxiogenic compounds (). In addition, CRF receptor antagonists block the anxiogenic actions of CRF in the rat (). Chlordiazepoxide also attenuates anxiogenic-like effects of CRF (), whereas acute and chronic administration of alprazolam decreases CRF concentration in the locus coeruleus (). These results have led to the hypothesis that administration of benzodiazepines to patients with anxiety and panic disorder may reduce central sympathetic hyperactivity by facilitating the inhibitory action of GAB A on the firing of CRF neurons innervating the locus coeruleus ().
The anxiolytic potential of neuropeptide Y, a 36-amino acid peptide with a broad distribution in the central nervous system, has been demonstrated in both animal and human studies (). The most likely anxiolytic action of neuropeptide Y is mediated through activation of Yl subtype of neuropeptide Y receptors in the central nucleus of the amygdala and is similar to the action of established anxiolytics ().
The neuropeptide galanin is functionally related to neuropeptide Y and is present in limbic brain areas important for emotionality. Galanin also has been observed to possess specific anxiolytic-like actions similar to those of neuropeptide Y ().
Excitatory Amino Acid Receptors
Animal research has revealed that antagonists, such as ketamine, phencyclidine, and dizocilpine (MK-801), at the NMDA receptor channel complex are clearly anxiolytic in animal models of anxiety. Because of the risk of abuse with phencyclidine-related drugs, which are thought to act at a site within the channel itself, antagonists at another site associated with the NMDA receptor channel complex — namely, those that act at the glycine-modulatory site on the NMDA receptor — are believed to have promise in the development of future anxiolytics ().
Overview of New Anxiolytics: Conclusion
Advances in the neurobiology of anxiety are coming at a rapid pace and are based on improvement in understanding both the biochemical pharmacology and the behavioral pharmacology of neurotransmitters, neuropeptides, and their multiple receptor subtypes. Exploiting these advances is leading to the development of multiple novel pharmacological agents that hold the potential of becoming the next generation of anxiolytic drugs. Specifically, partial agonists for the benzodiazepine receptor; selective agents for 5-HT1A, 5-HT2A, 5-HT2C, and 5-HT3 receptors; as well as selective agents for neuropeptide receptors such as CCK-B, CRT, and neuropeptide Yl may prove to be the basis for improved treatments of anxiety in the future.
Selections from the book: “Pharmacotherapy for Mood, Anxiety, and Cognitive Disorders”, 2000.