Behavioral Characterization of the Novel GABAB Receptor-Positive Modulator GS39783 (N,N′-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): Anxiolytic-Like Activity without Side Effects Associated with Baclofen or Benzodiazepines

Psychiatry Program, Neuroscience Research, The Novartis Institutes for BioMedical Research WSJ 386.344, Novartis Pharma AG, Basel CH-4002, Switzerland.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 10/2004; 310(3):952-63. DOI: 10.1124/jpet.104.066753
Source: PubMed


The role of GABAB receptors in various behavioral processes has been largely defined using the prototypical GABAB receptor agonist baclofen. However, baclofen induces sedation, hypothermia and muscle relaxation, which may interfere with its use in behavioral paradigms. Although there is much evidence for a role of the inhibitory neurotransmitter GABA in the pathophysiology of anxiety, the role of GABAB receptors in these disorders is largely unclear. We recently identified GS39783 (N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine) as a selective allosteric positive modulator at GABAB receptors. The aim of the present study was to broadly characterize the effects of GS39783 in well-validated rodent models for motor activity, cognition, and anxiety. The following tests were included: locomotor activity in rats and mice, rotarod and traction tests (including determinations of core temperature) in mice, passive avoidance in mice and rats, elevated plus maze in rats, elevated zero maze in mice and rats, stress-induced hyperthermia in mice, and pentobarbital- and ethanol-induced sleep in mice. Unlike baclofen and/or the benzodiazepine chlordiazepoxide, GS39783 had no effect in any of the tests for locomotion, cognition, temperature, or narcosis. Most interestingly, GS39783 had anxiolytic-like effects in all the tests used. Overall, the data obtained here suggest that positive modulation of GABAB receptors may serve as a novel therapeutic strategy for the development of anxiolytics, with a superior side effect profile to both baclofen and benzodiazepines.

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Available from: Klemens Kaupmann, Jan 04, 2016
    • "In contrast, pretreatment of baclofen at a dose of 20 mg/kg 30 min before cerebral ischemia in Sprague-Dawley rats significantly decreased the neuronal degeneration[25]. Baclofen in higher doses may be neuroprotective but its utility is complicated by postischemic hypertension, cerebral haemorrhages[24]and other side effects[26,27], which means that baclofen has a very narrow pharmacological efficacy window. The side effects of theIn addition, we did not observe any side effects in animals up to dose of 50 mg/kg of R-phenibut. "
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    ABSTRACT: R-phenibut is a γ-aminobutyric acid (GABA)-B receptor and α2-δ subunit of the voltage-dependent calcium channel (VDCC) ligand. The aim of the present study was to test the effects of R-phenibut on the motor, sensory and tactile functions and histological outcomes in rats following transient middle cerebral artery occlusion (MCAO). In this study, MCAO was induced by filament insertion (f-MCAO) or endothelin-1 (ET1) microinjection (ET1-MCAO) in Male Wistar or CD rats, respectively. R-phenibut was administrated at doses of 10 and 50mg/kg for 14 days in the f-MCAO or 7 days in the ET1-MCAO. The vibrissae-evoked forelimb-placing and limb-placing tests were used to assess sensorimotor, tactile and proprioceptive function. Quantitative real time-PCR was used to detect brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) gene expression in the damaged brain hemisphere.Both f-MCAO and ET1-MCAO resulted in statistically significant impairment of sensorimotor function and brain infarction. R-phenibut at a dose of 10mg/kg significantly improved histological outcome at day 7 in the ET1-MCAO. R-phenibut treatment at a dose of 50mg/kg significantly alleviated reduction of brain volume in damaged hemisphere in both f-MCAO and ET1-MCAO. In R-phenibut treated animals a trend of recovery of tactile and proprioceptive stimulation in the vibrissae-evoked forelimb-placing test was observed. After R-phenibut treatment at a dose of 50mg/kg statistically significant increase of BDNF and VEGF gene expression was found in damaged brain hemisphere. Taken together, obtained results provide evidence for the neuroprotective activity of R-phenibut in experimental models of stroke. These effects might be related to the modulatory effects of the drug on the GABA-B receptor and α2-δ subunit of VDCC.
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    • "The elevated plus maze is one of the most commonly rodent tests of anxiety and was performed as previously described (Cryan et al., 2004). The maze consisted of two open arms (51 × 10 cm) and two enclosed arms (51 × 10 × 41 cm) that all extended from a common central platform (10 × 10 cm). "
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    ABSTRACT: Stressful life events, especially those in early life, can exert long-lasting changes in the brain, increasing vulnerability to mental illness especially in females. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) play a critical role in the development and function of the central nervous system (CNS). Thus, we investigated the influence of an eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) (80% EPA, 20% DHA) n-3 PUFAs mixture on stress-related behavioural and neurobiological responses. Sprague-Dawley female rats were subjected to an early-life stress, maternal separation (MS) procedure from postnatal days 2 to 12. Non-separated (NS) and MS rats were administered saline, EPA/DHA 0.4g/kg/day or EPA/DHA 1g/kg/day, respectively. In adulthood, EPA/DHA treated animals had a dose dependent reduction in anxiety in NS rats. Furthermore, cognitive performance in the novel object recognition task (NOR) was improved by EPA/DHA treatment in NS animals only. EPA/DHA 1g/kg/day decreased behavioural despair in the forced swim test. Notably, EPA/DHA high dose increased the translocation of GRs into the nucleus of NS rat hippocampus. However, the levels of mBDNF remained unchanged in all the experimental groups. The corticosterone response to an acute stress was blunted in MS rats and this was further attenuated by pre-treatment with EPA/DHA. Immune response and monoamine neurotransmission were significantly altered by early-life stress. In conclusion, our study supports the view that n-3 PUFAs are beneficial in neurodevelopmentally normal animals but have little positive benefit in animals exposed to early life stress. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Apr 2015 · Psychoneuroendocrinology
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    • "We used two GABAB positive modulators, GS39783 and CGP7930, and mGlu5 PAM, CDPPB. GS39783 potentiates the effects of GABA on [ 35 S]GTPγS binding at recombinant and native GABAB receptors (EC50 values are 2.1 and 3.1 μM respectively) (Cryan et al., 2004; Mombereau et al., 2007; Urwyler et al., 2003). CGP7930 also Fig. 6. "
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    ABSTRACT: Diverse preclinical studies exploiting the modulation of the GABAergic and/or glutamatergic system in brain via metabotropic receptors suggest their potential therapeutic utility. GS39783 and CDPPB, a positive allosteric modulators of GABAB and mGlu5 receptors, were previously shown to reverse behavioral phenotypes in animal models thought to mimic selected (predominantly positive) symptoms of schizophrenia. In the present study we investigated the activity of selected GABAB (GS39783 and CGP7930) and mGlu5 (CDPPB) positive allosteric modulators. We focused mainly on the aspects of their efficacy in the models of negative and cognitive symptoms of schizophrenia. We used modified swim test, social interactions (models of negative symptoms) and novel object recognition (model of cognitive disturbances). The activity of the compounds was also tested in haloperidol-induced catalepsy test. The mutual interaction between GABAB/mGlu5 ligands was investigated as well. In the second part of the study, DHPG-induced PI hydrolysis in the presence of GABAB receptor antagonist (SKF97541), and SKF97541-induced inhibition of cAMP formationin the presence of DHPG, were performed. Both mGlu5 and GABAB receptor modulators effectively reversed MK-801-induced deficits in behavioral models of schizophrenia. Moreover, the concomitant administration of sub-effective doses of CDPPB and GS39783, induced a clear antipsychotic-like effect in all the procedures used, except DOI-induced head twitches. The concomitant administration of group I mGlu and GABAB agonists did not displayed any synergistic effects in vitro. Summing up, an activation of both types of receptor may be a promising mechanism for the development of novel antipsychotic drugs, efficacious towards positive, negative and cognitive symptoms. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Apr 2015 · Neurochemistry International
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