Synthesis and Pharmacological Characterization of 2-(Acylamino)thiophene Derivatives as Metabolically Stable, Orally Effective, Positive Allosteric Modulators of the GABA_B Receptor

Abstract

Two recently reported hit compounds, COR627 and COR628, underpinned the development of a series of 2-(acylamino)thiophene derivatives. Some of these compounds displayed significant activity in vitro as positive allosteric modulators of the GABAB receptor by potentiating GTPγS stimulation induced by GABA at 2.5 and 25 μM while failing to exhibit intrinsic agonist activity. Compounds were also found to be effective in vivo, potentiating baclofen-induced sedation/hypnosis in DBA mice when administered either intraperitoneally or intragastrically. Although displaying a lower potency in vitro than the reference compound GS39783, the new compounds 6, 10, and 11 exhibited a higher efficacy in vivo: combination of these compounds with a per se nonsedative dose of baclofen resulted in shorter onset and longer duration of the loss of righting reflex in mice. Test compounds showed cytotoxic effects at concentrations comparable to or higher than those of GS39783 or BHF177.

Ligand-guided homology modelling of the GABAB2 subunit of the GABAB receptor

“…51 inactive analogues of the PAMs in clusters 2 and 3 were identified from the scientific literature (S2 Table) [36,37]. In addition, 2536 property-matched decoys (presumed inactive compounds with similar physicochemical properties but dissimilar 2D topology compared with the actives) were selected from the ZINC database [38] using an in-house script that followed the Directory of useful decoys (DUD) methodology [39].…”

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

“…to reduce operant, oral alcohol self-administration in selectively bred, alcohol-preferring Indiana P rats. 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).…”

New paradigms in GPCR drug discovery

“…For example, allosteric modulation of the metabotropic glutamate receptor 5 (mGluR5, PAMs and NAMs [110]) and γ-aminobutyric acid receptor B (GABA B R, PAMs [108]) is being explored mainly for CNS disorders, and other allosteric modulators such as GLP-1R PAMs are intended for treating diabetes and other conditions [92–94]. The identification of the first allosteric GPCR modulators was empirical, decades before the receptor structures were elucidated, and in some cases we now understand their structural basis.…”