CGP7930: A positive allosteric modulator of the GABAB receptor

University of Melbourne, Melbourne, Victoria, Australia
CNS Drug Reviews (Impact Factor: 4.92). 02/2007; 13(3):308-16. DOI: 10.1111/j.1527-3458.2007.00021.x
Source: PubMed


CGP7930 (3-(3',5'-Di-tert-butyl-4'-hydroxy)phenyl-2,2-dimethylpropanol) is a positive allosteric modulator of the metabotropic GABAB receptor. CGP7930 has been found to modulate the GABAB receptor in the open, or high affinity, state increasing agonist affinity for the receptor and signal transduction efficacy following agonist stimulation. The GABAB heteromeric subunit B2, involved in signal transduction but not ligand binding, seems to be the site of action of CGP7930 and similar allosteric modulators. When administered alone in naïve animals, CGP7930 acts as an anxiolytic in rodents without other overt behavioral effects and has also been demonstrated to reduce self-administration of nicotine, cocaine, or alcohol in rodents, suggesting that "fine tuning" of the GABAB receptor by positive allosteric modulators may be able to regulate abuse of these drugs. Baclofen, the GABAB agonist, is currently finding use in treating addiction and various other disorders, but this can result in off-target effects and tolerance. CGP7930 when co-administered with baclofen enhances its potency, which could in theory minimize deleterious effects. Further study of CGP7930 is required, but this compound, and others like it, holds potential in a clinical setting.

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Available from: Andrew J Lawrence, Sep 24, 2014
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    • "The first synthesized and well-characterized GABAB receptor PAMs were CGP7930 and its analog CGP13501 (Urwyler et al., 2001). In vitro studies indicate that CGP7930 enhances GABA B receptor-stimulated [ 35 S]GTPgS binding in cultured cells and rat brain membranes by increasing the potency and efficacy of GABA (Urwyler et al., 2001; see Adams and Lawrence, 2007; Froestl, 2010). In membrane fractions of HEK293 cells, the EC 50 for GABA was increased 3-fold by 0.1 nM CGP7930 and 10-fold by 1.0 nM CGP7930, while the compound alone produced no significant effect on basal [ 35 S]GTPgS binding (Binet et al., 2004). "
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    ABSTRACT: γ-Aminobutyric acid B (GABAB) receptors and their ligands are postulated as potential therapeutic targets for the treatment of several brain disorders, including drug dependence. Over the past fifteen years positive allosteric modulators (PAMs) have emerged that enhance the effects of GABA at GABAB receptors and which may have therapeutic effects similar to those of agonists but with superior side-effect profiles. This review summarizes current preclinical evidence supporting a role of GABAB receptor PAMs in drug addiction in several paradigms with relevance to reward processes and drug abuse liability. Extensive behavioral research in recent years has indicated that PAMs of GABAB receptors may have a therapeutic efficacy in cocaine, nicotine, amphetamine and alcohol dependence. The magnitude of the effects observed are similar to that of the clinically approved drug baclofen, an agonist at GABAB receptors. Moreover, given that anxiolytic effects are also reported with such ligands they may also benefit in mitigating the withdrawal from drugs of abuse. In summary, a wealth of data now supports the benefits of GABAB receptor PAMs and clinical validation is now warranted.
    Full-text · Article · Jun 2014 · Neuropharmacology
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    • "When administered via intraperitoneal or subcutaneous injections, these modulators attenuated motor seizures induced by either auditory stimulation or pentylenetetrazole , as well as cortical EEG discharges induced by local electrical stimulation. These findings are of great interest as these allosteric modulators are thought to target only activated GABAB receptors and have fewer side effects than full agonists (Adams and Lawrence 2007; Pin and Pr ezeau 2007; Froestl 2010). However, the above anticonvulsive observations were made largely in young animals with acute seizures. "
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    ABSTRACT: Abstract Disturbances of GABAergic inhibition are a major cause of epileptic seizures. GABA exerts its actions via ionotropic GABAA receptors and metabotropic G protein-coupled GABAB receptors. Malfunction of GABAA inhibition has long been recognized in seizure genesis but the role of GABAB receptors in controlling seizure activity is still not well understood. Here, we examined the anticonvulsive, or inhibitory effects, of GABAB receptors in a mouse model of hippocampal kindling as well as mouse hippocampal slices through the use of GS 39783, a positive allosteric GABAB receptor modulator, and CGP 55845, a selective GABAB receptor antagonist. When administered via intraperitoneal injections in kindled mice, GS 39783 (5 mg/kg) did not attenuate hippocampal EEG discharges, but did reduce aberrant hippocampal spikes, whereas CGP 55845 (10 mg/kg) prolonged hippocampal discharges and increased spike incidences. When examined in hippocampal slices, neither GS 39783 at 5 μmol/L nor the GABAB receptor agonist baclofen at 0.1 μmol/L alone significantly altered repetitive excitatory field potentials, but GS 39783 and baclofen together reversibly abolished these field potentials. In contrast, CGP 55845 at 1 μmol/L facilitated induction and incidence of these field potentials. In addition, CGP 55845 attenuated the paired pulse depression of CA3 population spikes and increased the frequency of EPSCs in individual CA3 pyramidal neurons. Collectively, these data suggest that GABABB receptors regulate hippocampal hyperexcitability by inhibiting CA3 glutamatergic synapses. We postulate that positive allosteric modulation of GABAB receptors may be effective in reducing seizure-related hyperexcitability.
    Full-text · Article · Apr 2014
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    • "ABBREVIATIONS: GHB, g-hydroxybutyrate; CGP7930, 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol; rac-BHFF, (R,S)-5,7-di-tert- butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one; BHF177, N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-4- pyrimidinamine; CGP35348, 3-aminopropyl(diethoxymethyl)phosphinic acid; CCK, cholecystokinin; CCK-8, sulfated cholecystokinin-octapeptide; GS39783, N,N9-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine; GTP(g) 35 S, guanosine 59-O-(3-[ 35 S]thiotriphosphate; MK-801, (5S,10R)-(1)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate. et al., 2001; Adams and Lawrence, 2007), N,N9-dicyclopentyl-2- methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (Urwyler et al., 2003), (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran -2-one (rac-BHFF) (Malherbe et al., 2008), N-[(1R,2R,4S)-bicyclo [2.2.1]hept-2-yl]-2-m ethyl-5-[4-(trifluoromethyl)phenyl]-4- pyrimidinamine (BHF177) (Guery et al., 2007; Maccioni et al., 2009), methyl-2-(1-adamantanecarboxamido)-4-ethyl-5-methylthiophene- 3-carboxylate and methyl-2-(cyclohexanecarboxamido)-4- ethyl-5-methyltiophene-3-carboxylate (Castelli et al., 2011), and 2-{1-[2-(4-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin- 7-yl]-2-piperidinyl}ethanol (Perdona et al., 2011)]. Their positive GABA B modulatory activity in vitro was evidenced by enhancing GABA, and, for all compounds except BHF177, also by enhancing the GABA B receptor agonist baclofen. "
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    ABSTRACT: GABA(B) receptor-positive modulators are thought to have advantages as potential medications for anxiety, depression, and drug addiction. They may have fewer side effects than GABA(B) receptor agonists, because selective enhancement of activated receptors could have effects different from nonselective activation of all receptors. To examine this, pigeons were trained to discriminate the GABA(B) receptor-positive modulator (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) from its vehicle. The discriminative stimulus effects of rac-BHFF were not mimicked by the GABA(B) receptor agonists baclofen and γ-hydroxybutyrate (GHB), not by diazepam, and not by alcohol, cocaine, and nicotine, whose self-administration has been reported to be attenuated by GABA(B) receptor-positive modulators. The discriminative stimulus effects of rac-BHFF were not antagonized by the GABA(B) receptor antagonist 3-aminopropyl (diethoxymethyl)phosphinic acid (CGP35348) but were attenuated by the less efficacious GABA(B) receptor-positive modulator 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl) phenol (CGP7930), suggesting the possibility that rac-BHFF produces its discriminative stimulus effects by directly activating GABA(B2) subunits of GABA(B) receptors. At a dose 10-fold lower than the training dose rac-BHFF enhanced the discriminative stimulus effects of baclofen, but not of GHB. This study provides evidence that the effects of GABA(B) receptor-positive modulators are not identical to those of GABA(B) receptor agonists. In addition, the results suggest that positive modulation of GABA(B) receptors does not produce discriminative stimulus effects similar to those of benzodiazepines, alcohol, cocaine, and nicotine. Finally, the finding that rac-BHFF enhanced effects of baclofen but not of GHB is consistent with converging evidence that the populations of GABA(B) receptors mediating the effects of baclofen and GHB are not identical.
    Preview · Article · Dec 2012 · Journal of Pharmacology and Experimental Therapeutics
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