Characterization of COR627 and COR628, Two Novel Positive Allosteric Modulators of the GABA_B Receptor

Abstract

The potential efficacy of GABA B receptor agonists in the treatment of pain, drug addiction, epilepsy, cognitive dysfunctions, and anxiety disorders is supported by extensive preclinical and clinical evidence. However, the numerous side effects produced by the GABA B receptor agonist baclofen considerably limit the therapeutic use of this compound. The identification of positive allosteric modulators (PAMs) of the GABA B receptor may constitute a novel approach in the pharmacological manipulation of the GABA B receptor, leading to fewer side effects. The present study reports the identification of two novel compounds, methyl 2-(1-adamantanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR627) and methyl 2-(cyclohexanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR628), which act as GABA B PAMs in 1) rat cortical membranes and 2) in vivo assay. Both compounds potentiated GABA-and baclofen-stimulated guanosine 5Ј-O-(3-[ 35 S]thio)-triphosphate binding to native GABA B receptors, while producing no effect when given alone. GABA concentration-response curves in the presence of fixed concentrations of COR627 and COR628 revealed an increase of potency of GABA rather than its maximal efficacy. In radioligand binding experiments [displacement of the GABA B receptor antago-, both COR627 and COR628 increased the affinity of high-and low-affinity binding sites for GABA, producing no effect when administered alone up to a concentration of 1 mM. In vivo experiments indicated that pretreatment with per se ineffective doses of COR627 and COR628 potentiated the sedative/hypnotic effect of baclofen. In conclusion, COR627 and COR628 may represent two additional tools for use in investigating the roles and functions of positive allosteric modulatory binding sites of the GABA B receptor.

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

“…Several compounds have been shown to have positive GABA B modulatory activity in vitro [e.g., 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol (CGP7930) (Urwyler 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.…”

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

“…Several compounds have been shown to have positive GABA B modulatory activity in vitro [2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol (CGP7930) (Urwyler et al, 2001;Adams and Lawrence, 2007), N, (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-methyl-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 (COR627), and methyl-2-(cyclohexanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR628) (Castelli et al, 2012)], evidenced by enhancing GABA, and, for all compounds except BHF177, also by enhancing the GABA B receptor agonist baclofen. In vivo results suggest positive GABA B receptor modulators to have anxiolyticand antidepressant-like properties in elevated-maze and forced-swimming tests, respectively (Cryan et al, 2004;Frankowska et al, 2007;Jacobson and Cryan, 2008).…”

Computational Advances for the Development of Allosteric Modulators and Bitopic Ligands in G Protein-Coupled Receptors

“…Castelli et al (75) reported two novel PAMs (COR627 and COR628) in 2011. They selected six metabotropic γ-aminobutyric acid B (GABA B ) receptor PAMs with diverse structures from literatures (76)(77)(78)(79), and generated a fivefeatures pharmacophore model, including three hydrophobic sites (H1-H3), one aromatic group (R), and one hydrogenbond donor (D).…”