Development of subtype selective GABAA modulators.

Merck Sharp & Dohme Research Laboratories, Terlings Park, Eastwick Road, Essex CM20 1QR, England.
CNS spectrums (Impact Factor: 1.3). 02/2005; 10(1):21-7.
Source: PubMed

ABSTRACT Drugs modulating gamma-aminobutyric acid (GABA) transmission via the benzodiazepine (BZ) site on the gamma-aminobutyric acid type A (GABAA) receptor have been in widespread use for more than 40 years to treat anxiety, epilepsy, and sleep disorders. These drugs have been shown to be safe, well tolerated, and effective although the mechanism by they produce a myriad of pharmacologic effects remains elusive. In recent years it has been discovered that, although the GABAA receptor is widely distributed in the brain, the substructure and composition of the receptor differs from between brain regions. Termed "GABAA receptor subtypes" their discovery leads to speculation that different subtypes may mediate specific effects of BZs such as anxiety or sedation. The phenotypic analysis of transgenic knock-in and knock-out mice in which particular GABAA receptors were rendered insensitive to the effects of BZ while others were unaffected confirmed this speculation. Subsequently, subtype-specific GABAA ligands were developed that, for example, retained the anxiolytic effects of BZs but were devoid of their sedative effects. Therefore, it may be possible to develop effective anxiolytic compounds that have a much reduced side-effect profile compared with existing drugs.

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    ABSTRACT: GABAA receptor (GABAAR) function is maintained by an endogenous phosphorylation mechanism for which the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is the kinase. This phosphorylation is specific to the long intracellular loop I2 of the α1 subunit at two identified serine and threonine residues. The phosphorylation state is opposed by an unknown membrane-bound phosphatase, which inhibition favors the phosphorylated state of the receptor and contributes to the maintenance of its function. In cortical nervous tissue from epileptogenic areas in patients with drug-resistant epilepsies, both the endogenous phosphorylation and the functional state of the GABAAR are deficient.
    PLoS ONE 06/2014; 9(6):e100612. · 3.53 Impact Factor
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    ABSTRACT: RATIONALE: Synthesis of ligands inactive or with low activity at α1 GABAA receptors has become the key concept for development of novel, more tolerable benzodiazepine (BZ)-like drugs. WYS8, a remarkably (105 times) α1-subtype selective partial positive modulator, may serve as a pharmacological tool for refining the role of α1 GABAA receptors in mediation of BZs' effects. OBJECTIVES: Here, the effects of WYS8 on GABA-induced currents and on diazepam-induced potentiation of recombinant BZ-sensitive GABAA receptors were studied in more detail. In addition, the behavioral profile of WYS8 (0.2, 1, and 10 mg/kg i.p.), on its own and in combination with diazepam, was tested in the spontaneous locomotor activity, elevated plus maze, grip strength, rotarod, and pentylenetetrazole tests. RESULTS: WYS8, applied at an in vivo attainable concentration of 100 nM, reduced the stimulation of GABA currents by 1 μM diazepam by 57 % at α1β3γ2, but not at α2β3γ2, α3β3γ2, or α5β3γ2 GABAA receptors. The administration of WYS8 alone induced negligible behavioral consequences. When combined with diazepam, WYS8 caused a reduction in sedation, muscle relaxation, and anticonvulsant activity, as compared with this BZ alone, whereas ataxia was preserved, and the anxiolytic effect of 2 mg/kg diazepam was unmasked. CONCLUSIONS: Hence, a partial instead of full activation at α1 GABAA receptors did not necessarily result in the attenuation of the effects assumed to be mediated by activation of these receptors, or in the full preservation of the effects mediated by activation of other GABAA receptors. Thus, the role of α1 GABAA receptors appears more complex than that proposed by genetic studies.
    Psychopharmacology 05/2013; 230(1). · 3.99 Impact Factor
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    ABSTRACT: Anxiety disorders can be treated successfully with benzodiazepines, which act by binding to a site on the γ-aminobutyric acid type A (GABAA) receptor and potentiating the inhibitory effects of GABA. In addition to anxiolytic effects, benzodiazepines also induce unwanted side effects, including motor coordination deficits, sedation, memory impairments, and abuse liability. In recent years, the discovery of subtypes of the GABAA receptor associated with specific effects of benzodiazepines has led to the hope of improved anxiolytic drugs. In this regard, experiments with transgenic mice and novel ligands have implicated GABAA receptors containing α2 and/or α3 subunits as playing a key role in the anxiolytic effects of benzodiazepines, but not other effects such as sedation. This review summarizes current research supporting a role for α2 and α3 subunit-containing GABAA receptors in anxiolysis, with an emphasis on the pharmacology of recently developed compounds displaying subtype selectivity. Ultimately, the identification of specific receptor subtypes associated with anxiolysis will hopefully shed light onto how the brain systems that regulate anxiety work in the absence of a pharmacological intervention. This information, in turn, should help in identifying, and ultimately treating, the underlying pathological states associated with anxiety disorders.
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