Editorial [ Hot Topic:The Indolylglyoxylamide Scaffold as an Useful Tool to Obtain Anxiolytic Agents (Guest Editors: Sabrina Taliani & Federico Da Settimo )]

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)....