THPP-1

THPP-1 (CAS No.: 1257051-63-0) is a potent, selective, and orally bioavailable small-molecule inhibitor of phosphodiesterase 10A (PDE10A), developed as a chemical probe for investigating cyclic nucleotide signaling in the central nervous system. It exhibits high affinity for PDE10A in the low nanomolar range for both human and rat enzymes, reflecting strong target engagement and selectivity within the phosphodiesterase family. By inhibiting PDE10A, THPP-1 elevates intracellular cAMP and cGMP levels, leading to enhanced phosphorylation of key proteins associated with synaptic plasticity in the striatum, including the AMPA receptor GluR1 subunit, extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB). These signaling effects underpin its utility in neuropharmacology research, particularly in studies of dopaminergic and glutamatergic pathways. In preclinical models, THPP-1 produces dose-dependent modulation of behaviors predictive of antipsychotic activity, such as attenuation of NMDA receptor antagonist-induced hyperlocomotion and conditioned avoidance responses, and has demonstrated pro-cognitive effects in rodent and non-human primate paradigms assessing recognition memory and executive function. Owing to its favorable pharmacokinetic profile in preclinical species, THPP-1 is widely used in cell-based assays and in vivo studies to explore PDE10A biology, neuropsychiatric disease mechanisms, and therapeutic target validation, with experimental concentrations or dosing regimens adjusted according to specific study designs.