Naokata Yokoyama

Chapter 1. Anti-Anxiety Agents and Sedative-Hypnotics

Publisher Summary In this chapter, the pharmacological actions of different anti-anxiety agents and sedative-aypnotics have been discussed with current references. Current evidence indicates that most anxiolytic and sedative-hypnotic drugs exert their pharmacological actions by binding to discrete neuronal recognition sites, consisting of benzodiazepine (BZ) “receptors”, gamma-aminobutyric acid (GABA) receptors, and chloride ion channels. Binding of benzodiazepines (BZs) to the molecular complex increases the efficiency of GABA in opening chloride channels. Drugs acting at each component of the complex are known and have been used to label their respective recognition sites with either agonists or antagonists. The possibility of BZ receptor heterogeneity continues to be explored because it provides a mechanism for finding selective drugs. The ability of muscimol to enhance the binding affinities of ligands for the BZ receptor, rather than the affinities per se, correlates with their hypnotic activity. Ligands for BZ receptors can be characterized as agonists, antagonists, or inverse agonists on the basis of their behavior in three in vitro binding assays. Blockade of pentylenetetrazole (PTZ) interoceptive discriminative stimulus (IDS) as a model for anxiolytic activity has been discussed in the chapter and found to be reliable. The pharmacology of zopiclone, an anxiolytic-hypnotic BZ receptor ligand, has been discussed in this chapter. The pharmacological profile of suriclone is that of a typical agonist, but its binding characteristics differ suggesting that this compound might bind to a novel site linked allosterically to the BZ receptor. Sedatives like loprazolam and flurazepam have been equieffective in patients with disturbed sleep pattern. The relationship between the effects of muscimol on BZ receptor binding and the hypnotic activity of nine BZs has beenexplained in the chapter. BZs, whose receptor bindings are strongly modulated by muscimol, possess potent hypnotic activity, suggesting that the BZ-GABA receptor complex is involved in the hypnotic activity of the BZ drugs.

Chapter 2. Anxiolytics, Anticonvulsants and Sedative-Hypnotics

Publisher Summary Public interest in anxiety has continued to increase, with over 13 million individuals in the United States being affected by this disorder. At the preclinical level, the emphasis has been on attempts to separate the various pharmacological actions of the benzodiazepines (i.e., anxiolytic, sedative, anticonvulsant, and muscle relaxant), into distinct processes mediated via different receptor subtypes, although this approach is more molecular than physiological. Concurrently based on the activity of buspirone and related compounds the mechanistic emphasis has switched to the role of serotonin in the etiology of anxiety. This chapter discusses Benzodiazepine receptor ligands—pyrazoloquinoline, CGS 9896, CGS 9895, β-CMC, SAS 646, the “hetrazepine,” brotizolam (WE 941), metaclazepam, (KC-2547), loflazepate (CM 6912), and some others. BZ receptor subtypes, peripheral BZ receptors, endogenous ligands, opiate and thyrotropin releasing hormone (TRH) receptor interactions have been detailed, also Serotonergic aspects of anxiety and the behavioral aspects—with the shift in focus from BZs to serotonergics and other factors—the classical conflict paradigms are proving to be inadequate as preclinical models of anxiety. As a result, acoustic startle, distress vocalization, aggression, brain stimulation reinforcement, and defense burying paradigms are undergoing evaluation, as are various neophobic models, including arm maze and open field behavior—sedative/hypnotics and anticonvulsants. A short note has been provided on some novel approaches to anxiety.