Phosphodiesterase 10A (PDE10A)

Class

Selective, brain-penetrant, orally active small-molecule PDE10A inhibitor (IC50 0.30 nM, >15,000-fold selectivity over other PDE isoforms). Originated at Takeda as TAK-063; acquired by Axsome Therapeutics (April 2026), which plans Phase 3-enabling work in schizophrenia and Tourette syndrome.

Pathway

PDE10A is highly expressed in striatal medium spiny neurons (MSNs) and degrades cAMP/cGMP downstream of dopamine D1/D2 receptor signaling; inhibition raises cAMP/cGMP levels, activating both direct- and indirect-pathway MSNs, which underlies its antipsychotic-like effect in preclinical models.

Phosphodiesterase 10A (PDE10A) is an enzyme that breaks down two intracellular signaling molecules, cyclic AMP (cAMP) and cyclic GMP (cGMP), inside a class of brain cells called medium spiny neurons that make up most of the striatum, a region central to motor control and reward processing. These neurons receive dopamine input through D1 and D2 receptors, and the downstream effects of that dopamine signaling depend heavily on cAMP and cGMP levels. By selectively blocking PDE10A, an inhibitor prevents the breakdown of these second messengers, raising their concentration and enhancing signaling through both the direct and indirect striatal pathways that dopamine normally influences in opposite directions. This dual, pathway-independent amplification distinguishes PDE10A inhibition from conventional dopamine receptor blockade, which acts on only one side of the circuit. Because striatal dopamine signaling is implicated in psychotic symptoms and in involuntary movement disorders, modulating PDE10A has been explored as a strategy for conditions such as schizophrenia and tics, including Tourette syndrome, where correcting the balance of striatal output circuits may reduce symptoms without directly antagonizing dopamine receptors themselves.