Katherine S. Takaki

Chapter 4. Melatonin Receptor Ligands and Their Potential Clinical Applications

Publisher Summary Molecular characterization of a family of melatonin ( N -acetyl-5-methoxytryptamine) receptors has provided the foundation for new avenues of exploration. While the receptor proteins have been expressed in heterologous expression systems, data regarding precise localization of these receptors throughout the central nervous system (CNS) and periphery and how localization varies with species is limited. Melatonin first isolated from bovine pineal gland extracts is present in all mammalian species. Radio-iodination of melatonin produces [ 125 I]-iodomelatonin, a high affinity, high specific-activity radioligand suitable for discrete localization and pharmacological characterization of the melatonin binding sites. The target of melatonins actions is thought to be the suprachiasmatic nucleus (SCN), a circadian clock in the suprachiasmatic nucleus of the hypothalamus, as an intact SCN, is necessary for melatonin to exert an effect on rodent circadian rhythms. The large number of melatonin receptor sequences available has prompted efforts to model receptor tertiary structure and to identify amino acid residues involved in ligand binding. All the models are based on the identification of key amino acids that can participate in hydrogen bonding to the methoxy group and to the amide of melatonin, both of which have been identified as critical interaction points for the molecule based upon structure–activity relationship (SAR) studies.

Chapter 5. Pharmacological Interventions in the Sleep Process

Publisher Summary This chapter analyzes the pharmacologlcal interventions in the sleep process. Insomnia is the term used to describe difficulties in initiating sleep, maintaining sleep, or obtaining a restorative sleep. It is a symptom that can arise for a multitude of reasons and represents a significant public health problem. About 40% of the individuals suffering from insomnia attempt to self-medicate with over-the-counter agents or alcohol, indicating that a clear need still exists for accepted, effective medications. Because the likelihood of severe or chronic insomnia increases with age, the management of insomnia in the geriatric population is also a significant concern. The benzodiazepines (BZs) remain the mainstay of hypnotic therapy. The BZs produce their effects by acting at benzodiazepine receptors (BZRs) that are allosteric modulatory sites of the GABA A receptor. The chapter overviews current research aimed at improved pharmacological intervention in the sleep process and discusses the concepts related to GABA A benzodiazepine receptor ligands and melatonin receptor ligands. Aenosine receptor ligands are described and an overview of histamine receptor ligands is also presented.