Preface

This hot topic issue of Current Drug Targets - CNS and Neurological Disorders focuses on the GABAergic system for the development of novel and improved therapeutic approaches. GABA (γ-aminobutyric acid) is the major inhibitory neurotransmitter system in the mammalian brain and has been implicated in a large variety of neurological and psychiatric disorders, including anxiety, epilepsy, sleep and cognitive impairment. GABA is formed by the α-decarboxylation of Lglutamic acid, a reaction catalysed by glutamic acid decarboxylase (GAD), an enzyme encoded by two distinct genes to produce GAD65 and GAD67. GABA is packaged into presynaptic vesicles using the vesicular GABA transporter and when a depolarising stimulus arrives at the presynaptic nerve terminal, the vesicle fuses with the presynaptic membrane and GABA is released into the synaptic cleft. The released GABA may interact with the ionotropic GABAA receptors or the metabotropic GABAB receptors [1] or the ionotropic GABAC receptor [2]. It should be noted that whilst the GABAC receptor has been argued to be a subtype of the GABAA receptor family [3], in this Special Issue we have retained the GABAC nomenclature to emphasize the distinct neuroanatomical distribution and pharmacology of this receptor population [4]. The action of GABA within the synapse is terminated by uptake into neurons and glia by the plasma membrane GABA transporters, of which four genes have been described. Finally, GABA is metabolised to succinic semialdehyde in a reaction catalysed by GABA-α- oxoglutarate transaminase (GABA-T). Given the key role of the GABA system in mediating a wide variety of CNS functions it is therefore not surprising that the various enzymes, transporters and receptors involved in GABA function and metabolism have attracted considerable attention as potential therapeutic targets which is reflected in this Special Issue. Of the various therapeutic sites of intervention in GABAergic neurotransmission, the GABAA receptor has received most attention. Indeed, based upon the number of recognition sites that the GABAA receptor possesses (such as the GABA, benzodiazepine, neurosteroid, barbiturate, ethanol, anaesthetic, loreclezole and convulsant binding sites), this receptor alone could merit a Special Issue. Nevertheless, based upon over 40 years of clinical experience with the benzodiazepines (BZs) and the corresponding elucidation of the molecular mechanisms by which they exert their effects, it is the BZ binding site which forms the basis of the discussions of the GABAA receptor, with the acceptance that this is a blinkered view of the therapeutic potential of this receptor based more upon limitations of space rather than scientific rationale. Thus, the clinical safety and efficacy of BZs coupled to the realization that their diverse pharmacological effects (including anxiolysis, sedation, myorelaxation, cognitive impairment and anticonvulsant activity) are exerted via interaction with GABAA receptors containing an α1, α2, α3 or α5 subunit has resulted in the search for compounds which only express certain aspects of their pharmacology. Fundamental to this is an understanding of which GABAA subtypes mediate which particular aspect of the BZ pharmacology; a topic discussed in the review of “Validation of GABAA receptor subtypes as potential drug targets by using genetically modified mice” by T.W. Rosahl. It summarizes transgenic approaches to validate novel and existing drug targets by dissecting out the various effects of BZs and other GABAA receptor modulators, such as anaesthetics, on individual GABAA receptor subtypes. For example, in the search for compounds which are anxiolytic but have reduced sedation, two approaches have been employed; the development of non-selective compounds which interact with the four subtypes of GABAA receptor but with reduced efficacy relative to the existing full agonists used in the clinic (non-selective partial agonists) and, more recently, compounds which selectively enhance the actions of GABA at those GABAA receptor subtypes (α2 and / or α3- containing receptors) involved in anxiety (subtype-selective compounds). J.R. Atack reviews the status of preclinical and clinical studies on such non-sedating anxiolytics in “Anxioselective compounds acting at the GABAA receptor BZ binding site”. The major challenge for such compounds remains the difficulty in translating a novel pharmacology in preclinical species, whether it is achieved via non-selective partial agonism or subtype selectivity, into a meaningful advantage in the clinic. In contrast to developing subtype selective agonists as non-sedating anxiolytics, the approach of developing inverse agonists which specifically target α5 subunit containing GABAA receptors is described in K.A. Maubach's review “GABAA receptor subtype selective cognition enhancers”. It is well accepted that cognitive performance declines with age and as the demographics of the world population shifts towards the elderly, there is an increasing largely unmet medical need for cognition enhancers not only for the symptomatic treatment of Alzheimer's disease but also the mild cognitive impairment associated with the normal aging process and which may be a prelude to Alzheimer's disease. Preclinical animal studies with α5 selective inverse agonists are intriguing in that they enhance cognitive performance in normal animals but as with the subtype selective non-sedating anxiolytics, the crucial issue remains that of translating efficacy in animals models into meaningful improvements in the clinic. A problem with extrapolating from the pharmacology of a compound in vitro to that observed at the level of the whole animal (behaviour) is the lack of an understanding of the neuronal circuitry involved. The effect of GABAA receptor modulation on specific neuronal populations, for example hippocampal interneurons and pyramidal cells, is discussed by A. Semyanov in his review entitled “Cell type specificity of GABAA receptor mediated signaling in the hippocampus”. The problems associated with the development of novel anticonvulsant drug strategies in the absence of a detailed understanding of their effects on neuronal networks are highlighted. Moreover, the emergence of extrasynaptic GABAA receptors as a neuronal population exerting tonic inhibitory effects within the CNS highlights their potential as novel anticonvulsant targets. Although drugs which are selective either for anatomically discrete neuronal populations or for extra-synaptic rather than synaptic receptors are currently not available, Dr. Semyanov presents a persuasive case that such compounds would represent novel and effective anticonvulants. For many years, the GABAB receptor lived in the shadow of the GABAA receptor. Thus, whilst molecular biologists described a large variety of GABAA receptor subunits which offered a bewildering array of potential subtypes, and despite being implicated in a wide variety of neurological and psychiatric disorders, GABAB receptors remained decidedly dull and boring in comparison with their more glamourous cousins. However, all that has changed with the relatively recent cloning of GABAB receptors [5] which has reinvigorated interest in these receptors as potential drug targets. The review “GABAB receptors as potential therapeutic targets” by C.-M. Vacher and B. Bettler provides a thorough update on the molecular composition, the physiology and pharmacology of GABAB receptors and ongoing and future drug discovery efforts in the field. However, initial reports of GABAB subtype-selective compounds have proved difficult to reproduce and currently the best approach for achieving subtype selectivity appears to rest with the differential anatomical localization of the GABAB(1a,2) and GABAB(1b,2) subtypes. GABAC receptors are the least studied of the three major classes of GABA receptors and G.A.R. Johnston and colleagues summarize their therapeutic potential in “GABAC receptor as drug targets”. Major indications for drugs acting on GABAC receptors are in the treatment of visual, sleep and cognitive disorders. It is suggested that due to their relatively low abundance and more restricted neuroanatomical distribution in the CNS, GABAC receptor-selective drugs may provide an alternative to drugs acting through the more widespread GABAA or GABAB receptors. The last review of this issue by A. Sarup and colleagues focus on “GABA transporters and GABA-transaminase as drug targets”. The use of tiagabin and vigabatrin (γ-vinyl GABA) as anticonvulsants demonstrate the clinical utility of GABA transporters and GABA-transaminase, respectively. Whilst GABA transaminase exists as a single gene product and would therefore appear to offer little opportunity for further therapeutic specificity, the differential localization of the four members of the GABA transporter family in either neuronal or glial tissue may offer the opportunity to selectively modulate distinct aspects of GABAergic neurotransmission. Overall, this issue provides an overview of the current scientific knowledge of the physiology and pharmacology of the GABAergic system and highlights the potential for therapeutic intervention at a variety of points in the GABAergic neurotransmission pathway. Moreover, whilst drugs acting at these various targets currently exist and emphasize their therapeutic utility in a variety of neuropsychiatric and neurological disorders, refinements based upon subtype selectivity and / or anatomical localization offer the potential of greater clinical specificity. Within the next 5 or so years it is hoped that at least some of these novel strategies will face the ultimate challenge; that of demonstrating efficacy in the clinic. [1] Hill, D.R.; Bowery, N.G. Nature, 1981, 290, 149-152. [2] Johnson, G.A.R. Trends Pharmacol. Sci., 1996, 17, 319-323. [3] Barnard, E.A.; Skolnick, P.; Olsen, R.W.; Möhler, H.; Sieghart, W.; Biggio, G.; Braestrup, C.; Bateson, A.N.; Langer, S.Z. Pharmacol. Rev., 1992, 50, 291-313. [4] Bormann, J. Trends Pharmacol. Sci., 2000, 21, 16-19. [5] Kaupmann, K.; Huggel, K.; Heid, J.; Flor, P.J.; Bischoff, S.; Mickel, S.J.; McMaster, G.; Angst, C.; Bittiger, H.; Froestl, W.; Bettler, B. Nature, 1997, 386, 239-46.