Pharmacological differences of GABAergic compounds: a pharmacodynamic characterization

Abstract

This thesis describes different ways of exploring the pharmacological and therapeutic effects of novel GABA-ergic and GABA-like agents in humans. Systematic pharmacodynamic evaluations, using well-characterised positive controls, can confirm or refute the unique pharmacological properties of GABAA-subtype selective drugs in healthy volunteers. Such studies can help to predict dosing regimens and therapeutic advantages of these drugs. The distribution of different GABAA-receptor subtypes provides clues for their functional relevance. This knowledge can be used to optimise the desirable and undesirable effect profiles of selective GABA-ergic drugs. Very little is still known about the pathophysiological relevance of GABA-systems in CNS-disorders, although GABA-ergic treatments are in use for a wide range of clinical conditions. The availability of novel compounds with well defined pharmacological characteristics can clarify the involvement of these mechanisms in normal or abnormal physiology. This thesis hopes to show that carefully designed studies, using a range of CNS-measurement that reflect different GABAergic systems, can aid in the development of new GABA-ergic drugs, and help to unravel the role of the different GABA-ergic systems in health and disease.