# 6,7-Dihalo-Benzothiadiazines as Potent and Selective AMPA Receptor Modulators for Cognitive Enhancement and Neuroprotection

## TL;DR

Scientists developed a new compound that enhances brain function and protects neurons by modulating AMPA receptors.

## Contribution

A new benzothiadiazine compound (BPAM363) with improved cognitive-enhancing and neuroprotective effects was identified.

## Key findings

- Compound 14o (BPAM363) shows robust cognitive-enhancing effects in vivo.
- BPAM363 has strong neuroprotective properties and improved pharmacological characteristics.
- Structure–activity relationship optimization led to better AMPA receptor modulation.

## Abstract

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA)
receptors are tetrameric ionotropic glutamate receptors that mediate
fast excitatory synaptic transmission in the brain and represent important
therapeutic targets for neurological disorders. Positive allosteric
modulators (PAMs) of AMPA receptors enhance rapid excitatory signaling
by increasing receptor’s sensitivity to glutamate and have
been widely explored as agents to improve cognitive function in central
nervous system (CNS) diseases. Structural modification of 3,4-dihydro-2H-1,2,4-benzothiadiazine
1,1-dioxides (BTDs) analogs is a key strategy to develop potent AMPAR
PAMs. A recent study reported a new pharmacomodulation strategy on
the benzene ring of BTDs through systematic structure–activity
relationship (SAR) optimization. This work led to the identification
of compound 14o (BPAM363), which exhibits improved pharmacological
properties, robust in vivo cognitive-enhancing and
neuroprotective effects. These findings provide valuable insight for
further development of AMPAR PAMs as therapeutic candidates for cognitive
disorders.