alpha5 positive allosteric modulator

An **alpha5 positive allosteric modulator (alpha5-PAM)** is a class of small-molecule therapeutics designed to selectively augment the function of $\gamma$-aminobutyric acid type A ($\text{GABA}_A$) receptors containing the $\alpha_5$ subunit ($\alpha_5\text{-GABA}_A\text{R}$). These receptors are highly enriched in the hippocampus and prefrontal cortex, where they reside primarily on the dendrites of pyramidal neurons and mediate tonic inhibition. By selectively enhancing GABAergic signaling through the $\alpha_5$ subunit, these modulators boost dendritic inhibition typically provided by somatostatin-expressing ($\text{SST}^+$) interneurons. This mechanism is designed to restore microcircuit function, promote neurogenesis, and reverse neuronal atrophy (such as dendritic shrinkage and spine loss) associated with chronic stress, aging, and amyloid deposition. Unlike non-selective benzodiazepines, $\alpha_5$-selective PAMs avoid the common side effects of sedation, motor impairment, and abuse liability. Prominent development in this class includes Damona Pharmaceuticals' lead clinical candidate DPX-101 (GL-II-73), which is being advanced for the treatment of cognitive deficits in major depressive disorder, schizophrenia, and Alzheimer's disease.

Other names

alpha5 GABAA receptor positive allosteric modulatoralpha-5 GABAA receptor positive allosteric modulatoralpha 5 GABAA receptor positive allosteric modulatoralpha5-GABAA receptor positive allosteric modulatoralpha-5-GABAA receptor positive allosteric modulatoralpha 5-GABAA receptor positive allosteric modulatoralpha5-PAMalpha-5-PAMalpha 5-PAMGABAA receptor alpha5 subunit positive allosteric modulatorGABAA receptor subunit alpha5 positive allosteric modulatorGABA-A receptor subunit alpha-5 positive allosteric modulatorGABA-A alpha5 PAMGABA-A alpha5 positive allosteric modulatorGABAA alpha5 PAMGABAA alpha5 positive allosteric modulatorGABAA receptor alpha5 PAMGABAA receptor subunit alpha5 PAMGABA-A receptor subunit alpha-5 PAM