Current Topics in Medicinal Chemistry - Volume 12, Issue 4, 2012

The Guest Editors would like to dedicate this issue to the memory of Prof. Antonio Da Settimo. His studies on the indole nucleus, which he began in 1959, paved the way for the development of indolglyoxylamides as a class of molecules with interesting biological activity. This field has been a major topic of research for our team for over 30 years and it continues to be so today. The members of the research group founded by Prof. Antonio Da Settimo remember him with genuine affection. He was an example of excellence in science and in life for all of them. Anxiety disorders represent the most prevalent psychiatric disorders. A considerable burden is associated with them, not only for individual sufferers, but also for the health care system. Because anxiety is regarded as an innate fear, the physical basis of anxiety resides in the neural circuity that is related to the fear response including the amygdala, the nucleus accumbens, the hippocampus, the ventromedial hypothalamus, and so on. Many neurotransmitters and receptors perform several tasks in the modulation of anxiety states and function in contrasting or in similar ways, but the two most widely prescribed classes of anxiolytic drugs are selective serotonin reuptake inhibitors (SSRIs), which target the serotonergic system, and benzodiazepines (Bzs), which are ligands for the GABAA/Benzodiazeine Receptor (BzR) binding site, and act as allosteric positive modulator of the GABA response. GABA interacts with the ligand-gated ion channel receptor, GABAA receptor (GABAA-R), and regulates the flow of chloride into the cell, causing neuron hyperpolarization. GABAA-Rs are assembled from a family of 19 homologous subunit gene products and form mostly hetero-oligomeric pentamers. The major isoforms of the GABAA-Rs contain , and subunits and show a regional heterogeneity that is associated with distinct physiological effects. A variety of allosteric ligands can modulate the response to GABA by binding at different sites on the GABAA-R complex. The Bz one is located at the / subunit interface. Bzs are commonly used in therapy for their effects as anxiolytic, anticonvulsants, myorelaxants and hypnotics. The broad range of pharmacological effects of classical Bzs are mediated by the selective activation of different GABAA-R subtypes: the 1 subunit containing (BzR) mediates sedation, the 2 and 3 subunit containing BzR mediates anxiolysis and myorelaxation, and the 5 subunit containing BzR mediates cognitive impairment. Based on the current understanding of the diversity of the GABAA-R family, the Bz binding site, from late eighties to nowadays, has become the target of extensive research programmes directed to the identification of new ligands displaying varying degrees of affinity- and efficacy-selectivity for the different GABAA/BzR-subtypes. The principal aim has been to discover ideal sedative-hypnotic agents (selective 1 agonists), anxiolytic agents (selective 2/ 3 agonists), or cognitive enhancers (selective 5 inverse agonists)....

Anxiety disorders represent the most prevalent psychiatric disorders. In addition, a considerable burden is associated with them, not only for individual sufferers, but also for the health care system. However, many patients who might benefit from treatment are not diagnosed or treated. This may partly be due to lack of awareness of the anxiety disorders by primary care practitioners and by the sufferers themselves. In addition, the stigma still associated with psychiatric disorders and lack of confidence in psychiatric treatments are factors leading to no/under recognition and treatment, or the use of unnecessary or inappropriate treatments. This paper aims to provide a comprehensive review of recommendations for the pharmacological treatment of two common anxiety disorders, in particular obsessive-compulsive disorder (OCD) and panic disorder (PD). The first-line treatments of OCD include medium-high doses of selective serotonin reuptake inhibitors (SSRIs) and clomipramine, a tricyclic (TCA) antidepressant with prevalent serotonergic activity. The recommended drugs for PD include SSRIs, TCAs and serotonin-norepinephrine reuptake inhibitors (SNRIs); in treatmentresistant cases, benzodiazepines like alprazolam may be used in patients with no history of addiction and tolerance. Other treatment options include irreversible and reversible monoamine-oxidase inhibitors, hydroxyzine, and others. Besides pharmacological treatments, some psychological strategies have been shown to be effective, in particular, cognitive behavior therapy (CBT) and other variants of behavior therapy that have been sufficiently investigated in controlled studies, and, therefore, will be reviewed herein.

Anxiety disorders have been linked to alterations in γ-aminobutyric acid (GABA) neurotransmission. GABA interacts with the ligand-gated ion channels, GABAA receptor (GABAA-R) subtypes, and regulates the flow of chloride into the cell, causing neuron hyperpolarization. GABAA-Rs are assembled from a family of 19 homologous subunit gene products and form mostly hetero-oligomeric pentamers. The major isoforms of the GABAA-Rs contain α, β and γ subunits and show a regional heterogeneity that is associated with distinct physiological effects. A variety of allosteric ligands can modulate the response to GABA by binding at different sites on the GABAA-R complex. The bestcharacterized binding site is the benzodiazepine (BZ) one, which is located at the α/γ subunit interface. BZs are commonly used in therapy for their effects as anxiolytic, anticonvulsants, myorelaxants and hypnotics. The broad range of pharmacological effects of classical BZs are mediated by the selective activation of different GABAA-R subtypes: the α1 subunit containing BZ receptor (BZ-R) mediates sedation, the α2 and α3 subunit containing BZ-R mediates anxiolysis and myorelaxation, and the α5 subunit containing BZ-R mediates cognitive impairment. Based on the current understanding of the diversity of the GABAA-R family, different approaches have been employed to develop drugs that target the GABAA/BZ-R complex with selective anxiolytic action and improved profiles. In this review, we present current knowledge about the role of the GABAA/BZ-R complex in anxiety disorders, new insights into the molecular biology of the receptor complex, and the importance of this target in the development of new therapeutic agents in anxiety.

Neurosteroids are able to rapidly control the excitability of the central nervous system, acting as regulators of type A receptors for GABA. Over the last two decades, many authors have confirmed that neurosteroid level alterations occur in psychiatric disorders, including anxiety disorders. More recently, investigators have manipulated neurosteroidogenesis in an effort to correct neuronal excitation and inhibition imbalances, which may lie at the root of neuropsychiatric conditions. In line with this strategy, emerging data have demonstrated that a promising target for therapy of anxiety disorders is the Translocator Protein (TSPO). TSPO is a five transmembrane domain protein (18 kDa) that is expressed predominantly in steroid-synthesizing tissues. At the subcellular level, TSPO is localized at contact sites between the outer and inner mitochondrial membranes and mediates the rate-limiting step of neurosteroidogenesis. Brain concentrations of neurosteroids can be affected by selective TSPO activation. Indeed, TSPO drug ligands are able to stimulate the primary neurosteroid formations that enhance GABAA receptor activity, pregnenolone and allopregnenalone, both in in vitro steroidogenic cells and in vivo animal models. A spectrum of TSPO ligands has been shown to exert anxiolytic actions when administered in rodents. Some TSPO drug ligands could potentially reach clinical development. For example, recent evidence has shown that the selective TSPO ligand, XBD173 (AC-5216, Emapunil), exerts anxiolytic effects not only in animal models, but also in human volunteers. Herein, we review the current literature regarding the central nervous system biology of TSPO, a promising molecular target, in combination with its available ligands.

The classical benzodiazepines (Bz) constitute a well-known class of therapeutics displaying hypnotic, anxiolytic and anticonvulsant effects acting upon a specific binding site (BzR) belonging to the GABAA receptor complex. Their usefulness, however, is limited by a broad range of side effects; consequently the fact that the action of GABA with the receptor complex could be allosterically modulated by a wide variety of chemical entities, made the Bz binding site, from late eighties to nowdays, the target of extensive research programmes directed to the identification of new ligands displaying varying degrees of affinity- and efficacy-selectivity for the different GABAA/BzR-subtypes. The principal aim has been to discover ideal sedative-hypnotic agents (selective 1 agonists), anxiolytic agents (selective 2/ 3 agonists), or cognitive enhancers (selective 5 inverse agonists). In this connection, an important contribution in the field of GABAA/BzR ligands was made by the research group directed by Professor Antonio Da Settimo at the University of Pisa. The purpose of this review is therefore to describe the studies, performed from early '80s, on the several classes of BzR ligands developed featuring the indol-3-ylglyoxyl scaffold. All the compounds reported have been summarized on the basis of their main chemical structural features, focusing attention on their SARs, which determined the affinity profiles or efficacy-selectivity. Moreover, the biological studies performed within each class of compounds allowed the identification of new derivatives exhibiting an anxiolytic/nonsedative profile, either in vitro (full 2 agonism and 1 partial agonism/ antagonism) and in vivo (anxiolytic/nonsedative activity in mice).

Indolylglyoxylamides are a class of distinctive benzodiazepine receptor ligands, proposed in the mid-eighties as open analogues of -carbolines. Thorough and long-lasting studies of their structure-activity relationships led to the development of a great deal of derivatives, to satisfy increasingly structural and pharmacophoric requirements of the benzodiazepine binding site in the central nervous system. Efforts to pre-organize their flexible structure in the threedimensional shape adopted when bound to the receptor led to the identification of two novel classes of rigid ligands, characterized by planar tricyclic heteroaromatic cores: the [1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one and the [1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1,5(6H)-dione. The present review focuses on these selected classes of ligands, whose rational development, in terms of chemical structures and structure-activity relationships, will be fully discussed.

Interaction between the so-called benzodiazepine receptor (BzR) and the chemically heterogeneous class of its ligands is still one of the most challenging objects of theoretical studies. In the mid-90s our group began to collaborate with Prof. Antonio Da Settimo and coworkers to a project of synthesis and biological evaluation of indolylglyoxylamides designed as BzR ligands. Herein we review our efforts in designing these compounds and in interpreting their structureaffinity relationships. Our investigations were carried out for years by adopting the pharmacophore/topological model for BzR ligands set up by Cook's group. In an attempt to rationalize some puzzling structure-affinity relationships we speculated in 1998 that our ligands interact with the BzR by assuming one of two alternative binding modes (called “A” and “B”) depending on whether or not they were substituted at the 5-position of the indole nucleus. Such a model received support from a considerable amount of experimental data accumulated throughout our researches. About a decade later, docking calculations performed on a homology-built model of the 1 BzR subtype were found in agreement with the hypothesis of mode A and mode B of binding accessible to 5-H and, respectively, 5-Cl/NO2 indole derivatives.

The mitochondrial translocator protein (TSPO) mediates the synthesis of neurosteroids in the CNS, which have been demonstrated to enhance the neurotransmitter GABA response, exhibiting related behavioural properties. Selective TSPO ligands are able to stimulate steroidogenesis with great efficacy, thus representing potential anxiolytic agents. This review describes the development of a class of high affinity ligands to TSPO, N,N-dialkylindol-3-ylglyoxylamides (IGA), from the initial stages of design to the pharmacological characterization of selected compounds for their anxiolytic activity. Affinity data and SARs of the new class of ligands are discussed; the potential applications of compounds characterized by the indolylglyoxylyl scaffold in diagnostic imaging are also pointed out.

The Translocator Protein (18 kDa) (TSPO), previously known as the peripheral benzodiazepine receptor, is widely expressed in glial cells and in peripheral tissues and is involved in a variety of biological processes: steroidogenesis, cell growth and differentiation, apoptosis induction, etc. TSPO basal expression is up-regulated in a number of human pathologies, including a variety of tumors and neuropathologies, such as gliomas and neurodegenerative disorders (Huntington's and Alzheimer's diseases), as well as in various forms of brain injury and inflammation. Furthermore, changes in TSPO receptor levels have been found in anxiety and mood disorders. Nowadays, considerable efforts have been focused on the identification of new TSPO ligands characterized by high-affinity and selectivity. In this review, we report and analyze the main experimental data and the computational procedures and validation methods used for the construction of the TSPO receptor and ligand-based models, describing in detail the most successful results and the new trends.

Anxiety disorders are frequent and disabling disorders. For short-term treatment, benzodiazepines are useful due to their rapid onset of anxiolytic action. However, these compounds have sedative properties and may induce tolerance, abuse liability and withdrawal symptoms. First-line choices for the long-term treatment are selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors. The major disadvantage of these compounds is their delayed onset of action. It is obvious that there is a need for novel pharmacological approaches that combine a rapid anxiolytic efficacy with the lack of tolerance induction, abuse liability and withdrawal symptoms. A very important target for the development of such compounds is the -amino-butyric-acid (GABA)A receptor. Subtype specific benzodiazepines are being developed, but also phytotherapeutic agents experience a renaissance as GABAA receptor modulators. On the other hand, GABA related compounds, e.g. tiagabine, did not show pronounced anxiolytic efficacy. Neuroactive steroids such as allopregnanolone and tetrahydrodeoxycorticosterone (THDOC) are potent modulators of GABAA receptors. To date synthetic neuroactive steroids could not be established in the treatment of anxiety disorders. Regarding endogenous neurosteroidogenesis, recently the translocator protein (18kDa) (TSPO) has been identified as a potential novel target. TSPO is supposed to play an important role for the synthesis of neuroactive steroids. TSPO ligands may promote the synthesis of neuroactive steroids via induction of cholesterol translocation to the inner mitochondrial membrane. First clinical studies revealed promising results. In this review, we discuss putative compounds affecting the GABAergic system which may provide the basis for fast acting anxiolytics with a favorable side effect profile.