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At present, the only therapeutic agent in current use that is known to exert its effects through the GABA-B receptor is baclofen, the β-chlorophenyl analog of GABA. This compound is used extensively as a centrally active muscle relaxant, but it has been shown clinically to exert additional effects, including analgesia, suppression of drug addiction, and cessation of chronic cough. Basic research indicates that there may be many other applications not only for agonists, but also antagonists at the GABA-B receptor, and this chapter seeks to examine the potential significance of these and also of allosteric modulators for the receptor, which have been recognized during the past 5 yr. GABA-B receptors have been implicated in neuronal processing in many brain regions and there is considerable evidence for their pathological involvement in various diseases of the central nervous system, such as absence epilepsy, depression, and even in the etiology of nicotine dependency in humans. Novel chemical entities will surely be the key to exploiting this receptor. At present, the only agonist (baclofen) in the clinic frequently produces unwanted side effects, and this clearly limits its usage. There are no antagonists in clinical therapy, although trials for cognition deficits are underway. Metabotropic receptors, of which the GABA-B receptor is a member, provide most of the targets for our currently used therapeutic agents; thus, there seems to be every reason to believe that the rewards for discovering clinically available GABA-B receptor ligands could be high. [ABSTRACT FROM AUTHOR] more...

γ-Aminobutyric acid B (GABAB) receptors are the G protein-coupled receptors for the inhibitory neurotransmitter GABA. Cloning efforts revealed that functional GABAB receptors can be assembled from the products of the GABAB1 and GABAB2 genes. However, cloned receptors do not exhibit the reported functional and pharmacological diversity of native receptors, which led to speculations about the existence of additional GABAB receptor genes. Several groups now have generated mice with ablations in the GABAB1 and GABAB2 genes, which allowed studying the contributions of cloned gene products to pre- and postsynaptic GABAB functions. In this chapter, we review the phenotypes of GABAB knockout mice and discuss how genetic experiments have contributed to our current understanding of the GABAB receptor system. [ABSTRACT FROM AUTHOR] more...

Functional γ-aminobutyric acid (GABAB) receptors are formed by the association of GABABR1 and GABABR2, two closely related subunits belonging to the G protein coupled receptor superfamily. An increasing number of reports have now uncovered that GABAB receptors display unique functional properties, including unusual activation and inactivation mechanisms following binding of agonists. In this chapter the focus will be on nonclassical aspects of GABAB receptor phosphorylation, desensitization, downregulation, signaling, and association with a variety of protein partners. In addition, the extent to which the heterodimeric structure of the receptor contributes to establish these unusual properties will be discussed. [ABSTRACT FROM AUTHOR] more...

Nearly 10 yr have passed since the authors review "Chemistry of GABAB Modulators" appeared in the book "The GABA Receptors," 2nd edition, edited by S. J. Enna and N. G. Bowery, Humana Press, Totowa, 1997 (1). In this update the authors wish to outline only new developments not covered in the 1997 paper. Baclofen, synthesized for the first time in September 1962, is still the only γ-aminobutyric acid (GABAB)-receptor agonist marketed for the treatment of spasticity and trigeminal neuralgia. It is fascinating to learn how many highly competent chemists devised manifold and elegant synthetic procedures for either racemic or (R)-(−)-baclofen and the structurally closely related potent antidepressant (R)-(−)-Rolipram, a selective phosphodiesterase-4 inhibitor. The new syntheses published after 1996 are listed in alphabetical order (2-16). Very recently a prodrug of (R)-(−)-baclofen (Fig. 1) was described which enhanced the oral bioavailability in Cynomolgus monkeys to more than 80% (17). It is planned to test this prodrug in clinical trials for the treatment of spasticity and gastroesophageal reflux disease. [ABSTRACT FROM AUTHOR] more...

The γ-aminobutyric acid (GABA) neurotransmitter acting through ionotropic and metabotropic receptor classes exerts the major inhibitory control in the central nervous system. Therapeutic agents targeting GABA receptors (GABA-R), such as benzodiazepines and baclofen, are used to treat many nervous system conditions, including anxiety and spasticity. The subunit composition of GABA-Rs at the cell surface plays a critical role in determining their physiological and pharmacological properties, and alteration of GABA-R subunit expression has been associated with a number of diseases including schizophrenia, temporal lobe epilepsy, and alcoholism. The ionotropic type A GABA receptor (GABAAR) and type C GABA receptor (GABACR) are pentameric complexes that comprise a ligand gated chloride channel. The metabotropic type B GABA receptor (GABABR) is a heterodimer that couples G protein-signaling to GABA binding. There are eight classes of ionotropic receptor subunits and only two metabotropic receptor subunit classes. Most of the GABAAR subunit genes are localized in syntenic β-α-γ gene clusters on four chromosomes but the two GABABR genes are localized on distinct chromosomes. Control over subunit expression in different brain regions and during development is orchestrated at the genomic level by the use of multiple promoter regions and through the alternative splicing of GABA-R subunit RNAs. This chapter examines current GABA-R research relevant to the many levels of control over receptor gene regulation and cell surface receptor expression that may be relevant to both health and disease. [ABSTRACT FROM AUTHOR] more...

Ligands that act at γ-aminobutyric type A (GABAA) receptors, in particular the benzodiazepines and related drugs, have broad clinical use but also the liability for abuse and dependence. Recent epidemiological data suggest that abuse of benzodiazepine-type drugs may be on the upswing, with a shift from primary misuse of benzodiazepines by people in a therapeutic setting to use by younger people engaging in recreational abuse. Laboratory findings suggest that benzodiazepine-type drugs have reinforcing effects both in human and non-human subjects. However, benzodiazepine-type drugs appear to have lower reinforcing effectiveness compared to other drugs of abuse, such as psychomotor stimulants. Recent research has begun to explore the role of GABAA receptor subtypes in the reinforcing effects of benzodiazepine-type drugs, and unlike other behavioral effects (e.g., motor coordination deficits); reinforcing effects are not easily attributed to a single receptor subtype. Perhaps the most firm conclusion that can be made at this point is that stimulation of GABAA receptors containing α1 subunits (α1GABAA receptors) is not necessary for self-administration of benzodiazepine-type compounds. Benzodiazepine use also is associated with physical dependence, characterized by a withdrawal syndrome. In both human and non-human subjects, this withdrawal syndrome is considered to be intermediate in severity. Preliminary results suggest that compounds with selectivity for α2GABAA, α3GABAA, and/or α5GABAA receptors do not induce physical dependence. As with reinforcing effects, systematic studies with selective compounds having relatively high intrinsic efficacy at particular subtypes should shed light on theses important mechanistic issues. [ABSTRACT FROM AUTHOR] more...

Idiopathic generalized epilepsies (IGEs) are characterized by absence, myoclonic, and/or primary generalized tonic-clonic seizures in the absence of structural brain abnormalities and are believed to have a genetic basis. Mutations in γ-aminobutyric acid (GABAA) receptor γ2-, α1-, and δ-subunits have been associated with different IGE syndromes, and all of the γ2-subunit mutations are also associated with febrile seizures. Here, mutations in GABAA receptor γ2-, α1-, and δ-subunits that have been associated with different IGE syndromes will be reviewed and the basis for the defect in GABAergic inhibition associated with febrile seizures will be explored. These mutations have been shown to alter GABAA receptor gating, expression, and/or trafficking of the receptor to the cell surface, all pathophysiological mechanisms that result in reduced GABA-evoked currents that, in turn, would cause neuronal disinhibition in neurons and thus predispose affected patients to manifest afebrile and febrile seizures. [ABSTRACT FROM AUTHOR] more...

γ-Aminobutyric acid A (GABAA) receptor subunit multiplicity results in the generation of diverse receptor subtypes with distinct biophysical and pharmacological properties. These receptor subtypes show different subcellular targeting and can be activated by GABA in different ways, with different functional outcomes. Synaptic receptors underlie brief postsynaptic currents, whereas high-affinity, largely extrasynaptic, receptors generate a "tonic" conductance. These differences have implications for our understanding of normal brain function and the rational design of therapeutic agents. [ABSTRACT FROM AUTHOR] more...

γ-Aminobutyric acid (GABAA) receptors are the major inhibitory neurotransmitter receptors in the brain and are the site of action of many clinically important drugs. They are made up of five subunits that can belong to eight different subunit classes. Depending on their subunit composition these receptors exhibit distinct pharmacological and electrophysiological properties. The distinct but overlapping regional and cellular distribution of these subunits gives rise to the formation of a large number of GABAA-receptor subtypes, only a few of which so far have been unequivocally identified in the brain. Recent homology modeling of the structure of the extracellular and transmembrane domain of GABAA receptors for the first time provided a glimpse on the three-dimensional organization of this receptor, and placed different protein segments that have been shown to be of functional importance into a "region in space" and into defined neighboring relations. The models obtained could explain experimental observations and propose the location of putative drug-binding sites. They can be now used to design experiments for clarification of pharmacological and structural questions as well as to shed light on conformational changes during binding of agonist, gating, and allosteric modulation of these receptors. [ABSTRACT FROM AUTHOR] more...

γ-Aminobutyric acid receptors (GABAA Rs) are the principal receptors that mediate neural inhibition in the brain. Changes in the function of GABAergic transmission are implicated in activity-dependent adaptation of neural excitability. Of particular interest are mechanisms that control the size of the postsynaptic GABAA-receptor pool, a major determinant of synaptic strength. Mechanisms of trafficking of postsynaptic GABAA Rs contribute to regulation of inhibitory synaptic transmission in response to changes in neural activity and extracellular stimuli. This review summarizes current information available on the receptor structures relevant for trafficking of GABAA Rs, the molecular composition of the submembrane cytoskeleton of inhibitory synapses, and the receptor interacting proteins that regulate the localization and trafficking of postsynaptic GABAA Rs during exocytosis, lateral diffusion and endocytic recycling, and degradative pathways. [ABSTRACT FROM AUTHOR] more...

Oscillatory activities are hallmarks of neuronal network functions. They contribute to information processing in a multitude of brain activities including cognitive functions. A key requirement for the generation of network oscillations is regular and synchronized neuronal activity. The temporal structure and spatial coherence of network oscillations is largely controlled by GABAergic interneurons. To provide the appropriate response characteristics the synaptic specialization of these interneurons includes an extensive diversity of GABAA receptors. The cell- and domain-specific location of these receptor subtypes offers the possibility to gain functional insights into the role of defined neuronal circuits. Pharmacologically, neurons operating with α1 GABAA receptors mediate sedation while the small population of α2GABAA receptors largely mediates anxiolysis. Schizophrenia-related phenotypes can be ameliorated through α3GABAA receptors. Memory and learning are enhanced by diminishing α5GABAA receptor function. Thus, by targeting selective neuronal circuits GABAA receptor subtypes provide a new circuit-specific GABA pharmacology for a multitude of CNS dieases. [ABSTRACT FROM AUTHOR] more...

γ-Aminobutyric acid (GABA), an amino acid neurotransmitter, is widely distributed throughout the neuraxis. Two pharmacologically and molecularly distinct GABA receptors have been identified, GABAA and GABAB. GABAA receptors are pentameric ligand-gated chloride-ion channels, whereas GABAB receptors are heterodimeric G protein-coupled sites. Although GABAA receptor subtypes can display pharmacological differences, the two molecularly distinct GABAB receptors have similar substrate specificities, limiting the ability to selectively manipulate this site. Gene deletion and point mutation studies have revealed the importance of GABA receptors in neural development and function, with subtle modifications in subunit amino acid composition having profound effects on behavioral phenotype and responses to drugs. The characterization of GABAA receptors has contributed substantially to the knowledge about allosteric regulation of ligand-gated ion channels. Such information is invaluable in defining precisely the mechanisms of action of numerous drugs, such as the benzodiazepines, and toxic agents. Research on GABAB receptors has proven the existence of dimeric metabotropic receptors and has provided the chemical tools necessary for defining such systems. The characterization of the pentameric GABAA and dimeric GABAB receptors has been crucial for understanding the neurobiological basis of some nervous system disorders. Given the importance of GABA in central nervous system function, further work on its receptors is likely to yield novel therapeutics for treating a host of neurological and psychiatric conditions. [ABSTRACT FROM AUTHOR] more...