THE CGP7930 ANALOGUE 2,6‐DI‐<i>TERT</i>‐BUTYL‐4‐(3‐HYDROXY‐2‐SPIROPENTYLPROPYL)‐PHENOL (BSPP) POTENTIATES BACLOFEN ACTION AT GABA<sub>B</sub> AUTORECEPTORS

2012

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 g-hydroxybutyrate (GHB), not by diazepam, and not by alcohol, cocaine, and nicotine, whose selfadministration 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 receptorpositive 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.

Section: Discussionsupporting

confidence: 63%

Discriminative Stimulus Effects of the GABA_B Receptor-Positive Modulator rac-BHFF: Comparison with GABA_B Receptor Agonists and Drugs of Abuse

Koek

2012

“…Therefore, the differential enhancement of effects of baclofen and GHB by the GABA B receptor modulators rac-BHFF and CGP7930 may not involve agonist-dependent enhancement of a single population of GABA B receptors, but may result from preferential modulation of different GABA B receptor populations. Consistent with this latter possibility, in vitro evidence shows that CGP7930 preferentially potentiates activity at GABA B autoreceptors, but not at GABA B heteroreceptors Parker et al, 2008). Such receptor heterogeneity would allow more selective manipulation of the GABA B system.…”

Section: Discussionsupporting

confidence: 57%

“…Preferential activity of GHB at GABA B heteroreceptors on glutamatergic neurons and baclofen at GABA B autoreceptors on GABAergic neurons could conceivably account for some of these differences (Carter et al, 2009). In vitro evidence suggests that CGP7930 potentiates activity at GABA B autoreceptors, but not at heteroreceptors Parker et al, 2008). This suggests the possibility that CGP7930 preferentially enhances the in vivo effects of baclofen compared with GHB.…”

Section: Introductionmentioning

confidence: 85%

Effects of the GABA_B Receptor-Positive Modulators CGP7930 and rac-BHFF in Baclofen- and γ-Hydroxybutyrate-Discriminating Pigeons

Koek¹,

2012

In vivo effects of GABA B receptor-positive modulators suggest them to have therapeutic potential to treat central nervous system disorders such as anxiety and drug abuse. Although these effects are thought to be mediated by positive modulation of GABA B receptors, such modulation has been examined primarily in vitro. This study further examined the in vivo properties of the GABA B receptor-positive modulators 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl) phenol (CGP7930) and (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF). In pigeons discriminating baclofen from saline, ␥-hydroxybutyrate (GHB) produced 100% baclofen-appropriate responding, and the GABA B antagonist 3-aminopropyl(dimethoxymethyl) phosphinic acid (CGP35348) blocked the effects of both drugs. CGP7930 and rac-BHFF produced at most 41 and 74% baclofen-appropriate responding, respectively, and enhanced the discriminative stimulus effects of baclofen, but not of GHB. In pigeons discriminating GHB from saline, CGP7930 and rac-BHFF produced at most 1 and 49% GHB-appropriate responding, respectively, and enhanced the effects of baclofen, but not of GHB. Enhancement of the discriminative stimulus effects of baclofen by rac-BHFF and CGP7930 is further evidence of their effectiveness as GABA B receptor-positive modulators in vivo. Furthermore, lack of complete substitution of the positive modulators rac-BHFF and CGP7930 for baclofen and GHB suggests that their discriminative stimulus effects differ from those of GABA B receptor agonists. Finally, together with converging evidence that the GABA B receptor populations mediating the effects of baclofen and GHB are not identical, the present findings suggest that these populations differ in their susceptibility to positive modulatory effects. Such differences could allow for more selective therapeutic targeting of the GABA B system.

“…Based on the results of the present experiments, it is tempting to speculate that the pharmacological properties of these receptor populations differ as well. Differential enhancement of GABA B receptor populations by positive modulators has been shown in vitro: presynaptic GABA B autoreceptors seem to be sensitive to CGP7930 and the CGP7930 analog BSPP, whereas presynaptic GABA B heteroreceptors are not Parker et al, 2008). Conceivably, such differential enhancement could also be involved in the in vivo effects of CGP7930 and rac-BHFF reported here.…”

Section: Discussionmentioning

confidence: 59%

“…Preferential activity of GHB at GABA B heteroreceptors on glutamatergic neurons and preferential activity of baclofen at GABA B autoreceptors on GABAergic neurons could conceivably account for some of these differences (Carter et al, 2009). Recent in vitro evidence suggests that CGP7930 and its analog 2,6-di-tert-butyl-4-(3-hydroxy-2-spiropentylpropyl)-phenol (BSPP) selectively potentiate activity at GABA B autoreceptors, but not at heteroreceptors Parker et al, 2008). This suggests the possibility, examined here, that CGP7930, and perhaps rac-BHFF, preferentially enhance in vivo effects of baclofen compared with those of GHB.…”

Section: Introductionmentioning

confidence: 99%

GABA_B Receptor-Positive Modulators: Enhancement of GABA_B Receptor Agonist Effects In Vivo

Koek

2010

In vivo effects of GABA B receptor-positive modulators suggest that they have therapeutic potential for treating central nervous system disorders such as anxiety, depression, and drug abuse. Although these effects generally are thought to be mediated by positive modulation of GABA B receptors, such modulation has been examined primarily in vitro. The present study was aimed at further examining the in vivo positive modulatory properties of the GABA B receptor-positive modulators, 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl) phenol (CGP7930) and (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF). Both compounds enhanced loss of righting induced by baclofen in mice. However, CGP7930 was less effective and rac-BHFF was less potent for enhancing loss of righting induced by ␥-hydroxybutyrate (GHB), which, like baclofen, has GABA B receptor agonist properties. In contrast with baclofen-and GHB-induced loss of righting, the hypothermic effects of baclofen and GHB were not enhanced by rac-BHFF but were enhanced by CGP7930 only at doses that produced hypothermia when given alone. CGP7930-induced hypothermia was not attenuated by the GABA B receptor antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP35348), at doses that blocked baclofen-induced hypothermia, and was not increased by the nitric-oxide synthase inhibitor N -nitro-L-arginine methyl ester, at doses that increased the hypothermic effects of baclofen and GHB. The results provide evidence that CGP7930 and rac-BHFF act in vivo as positive modulators at GABA B receptors mediating loss of righting, but not at GABA B receptors mediating hypothermia. Conceivably, CGP7930, but not rac-BHFF, acts as an allosteric agonist at these latter receptors. Taken together, the results provide further evidence of pharmacologically distinct GABA B receptor subtypes, possibly allowing for a more selective therapeutic interference with the GABA B system.