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

Abstract

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.

Positive Allosteric Modulation of GABAB Receptors Ameliorates Sensorimotor Gating in Rodent Models

“…It is also worth mentioning that the same doses of rac ‐BHFF that elicited antipsychotic‐like effects in our models also failed to affect locomotor responses or other spontaneous behavioral manifestations in the home cage [R. Frau and V. Bini, unpublished observations]. Taken together, our findings complement previous preclinical data on the beneficial effects of GABA B R PAMs and highlight this class of compound as a novel putative avenue for antipsychotic therapy with fewer side effects than GABA B R antagonists.…”

Catalytic Asymmetric Synthesis of 3-Hydroxy-3-trifluoromethyl Benzofuranones via Tandem Friedel–Crafts/Lactonization Reaction

“…Recently, the 3-hydroxy-3-trifluoromethyl substituted benzofuran-2-ones have attracted increasing attention because of their remarkable medicinal and pharmaceutical activities partly due to the unique properties of the trifluoromethyl moiety . For example, 5,7-di- tert -butyl-3-hydroxy-3-trifluoromethyl-3 H -benzofuran-2-one (BHFF) was found to be a strikingly effective GABAB positive allosteric modulator and was demonstrated to have therapeutic potential to treat nervous system disorders . Notably, (−)-BHFF has proven to be more robust than (+)-BHFF and rac -BHFF by in vivo studies on Chinese hamsters .…”

Inhibition of alcohol self-administration by positive allosteric modulators of the GABAB receptor in rats: lack of tolerance and potentiation of baclofen

“…Additionally, several GABA B PAMs have been reported to potentiate multiple, in vivo pharmacological effects of baclofen, including hyperphagia (Ebenezer 2012), prevention of amphetamine-induced locomotor stimulation (Cedillo and Miranda 2013), inhibition of light-induced phase shifts of circadian activity (wheel running) rhythms (Gannon and Millan 2011), and sedation/ hypnosis (Carai et al 2004;Malherbe et al 2008;Koek et al 2010;Castelli et al 2012;Mugnaini et al 2013), in rats, mice, and hamsters. Finally, CGP7930 and rac-BHFF enhanced the discriminative stimulus effects of baclofen in pigeons trained in a baclofen drug discrimination procedure (Koek et al 2012).…”