LAUSR

Background and purpose: Since GABAergic dysfunction underlies a variety of neurological and psychiatric disorders, numerous strategies leading to the augmentation of GABAergic neurotransmission have been introduced. One of them is the inhibition of GABA reuptake from the synaptic cleft mediated by four plasma membrane GABA transporters (GAT1‐4). GAT1 which is exclusively expressed in the brain is an interesting target for centrally acting drugs. In this research, pharmacological properties of a novel, highly potent and selective inhibitor of GAT1, the guvacine derivative named DDPM‐2571, were assessed in vivo. Experimental approach: Pharmacological effects and pharmacokinetics of intraperitoneally administered DDPM‐2571 were assessed in CD‐1 mice. Key results: DDPM‐2571 was quickly distributed into the brain and was highly effective in the prevention of chemically‐induced seizures (pentylenetetrazole and pilocarpine models) and 6‐Hz convulsions. It demonstrated significant anxiolytic‐like and antidepressant‐like properties. DDPM‐2571 had antinociceptive properties, both in the hot plate test and in the second phase of the formalin test. Within the dose range tested, it did not impair animals' motor skills, but it impaired cognition and potentiated scopolamine‐induced cognitive deficits in the passive avoidance task. Conclusions and implications: Due to GAT1 inhibition, DDPM‐2571 is effective in mouse models of chemically‐induced seizures, anxiety, depression, acute and tonic pain. At biologically active doses, it does not impair animals' motor skills, but it might induce memory deficits. Taken together, DDPM‐2571 can be regarded as a promising lead structure in the search for new centrally acting drugs and a potent pharmacological tool to study the biological role of GAT1. Graphical abstract Figure. No caption available. HighlightsDDPM‐2571, a guvacine analogue, is a novel, potent inhibitor of GABA transporter GAT1.It has prominent anticonvulsant properties in chemically‐induced seizures in mice.It demonstrates anxiolytic‐like and antidepressant‐like properties in vivo.DDPM‐2571 has antinociceptive activity in acute and tonic pain models in mice.These pharmacological activities are observed at doses lower than those of tiagabine.