Structural Exploration around 4‑Cyclopropyl-Substituted 1,2,4-Benzothiadiazine 1,1-Dioxides: Impact of the Dihalo-Substitution of the Benzene Ring on α‑Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid (AMPA) Receptor Potentiation

The present study investigates the AMPA receptor potentiation and cognitive-enhancing effects of novel halosubstituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. Monohalosubstituted 4-cyclopropyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides were initially identified for their promising activity. In this article, a new pharmacomodulation explored the addition of a second halogen atom on the benzene nucleus and the variation of the cycloalkyl group at the 4-position. Compound 14o (the 6,7-dichloro-4-cyclopropyl-substituted derivative) was selected based on potency and safety. It selectively potentiated AMPA receptors in human and rat models, enhanced AMPA-mediated excitatory postsynaptic responses in rat hippocampal slices, and increased brain-derived neurotrophic factor (BDNF) expression in rat cortical neurons. In vivo, 14o in animal models significantly improved long-term potentiation (LTP) and enhanced cognitive performance in memory-related behavioral tasks at low doses. Notably, 14o also exhibited neuroprotective effects in rats, delaying hippocampal neurodegeneration following transient ischemia, without proconvulsant activity. These findings support 14o as a promising candidate for the treatment of cognitive disorders.