Accumulating data suggest that the GABAergic system may play a key role in beta-cell survival and regeneration in both type 1 and type 2 diabetes. Therefore, the development of new positive allosteric modulators of the GABAA receptors (GABAA-Rs) provides an interesting strategy for an antidiabetic therapy, although central nervous system side effects mediated by α1-GABAA-Rs are a potential concern. Here we synthesized and functionally analyzed a series of low molecular weight thioacrylamides (ThAcs), designed to both positively modulate GABAA-R signalling and show low blood brain barrier penetration. Beta-cell proliferation was increased by several ThAcs at nanomolar concentrations in a rat beta-cell line in vitro (i.e., ∼82% increased EdU incorporation after 24 hours treatment with ThAc HK-4 at 100 nM). The most effective candidate, HK-4, was further characterized. By using radio ligand competition assays and functional patch clamp experiments we analyzed the interaction between HK-4 and GABAA-Rs. In competition assays, we observed a dose-dependent affinity of HK-4 for GABAA-Rs in rat cortical neuron membranes. In electrophysiological patch clamp assays, we determined the modulating activity of HK-4 to individual human GABAA-Rs using HEK293 cells stably expressing different subunit combinations. HK-4 induced very strong potentiation of the current elicited by the natural ligand GABA on GABAA receptors containing combinations of α2β3γ2 (current ∼300% of GABA alone), α3β3γ2 (∼770%) and on α1β3γ2 (∼580%) subunits, respectively. Minimal blood brain barrier penetration of HK-4 was verified by mass spectrometry-based analyses of brain and plasma samples of rats. Additionally, HK-4 shows no major toxicological effects as determined in a 90-day toxicity study with daily dosing, has a favorable pharmacokinetic profile and demonstrates good oral bioavailability. Our data reveal the potential of HK-4 and other ThAcs for further development into antidiabetic drugs.


B. Hasse: Stock/Shareholder; Self; Algiax Pharmaceuticals GmbH. B. Belgardt: None. M. Hecht: None. R. Wördenweber: None. A. Piechot: None. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S. J. Eckel: None.


EFRE; NRW; European Union

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