MR1916

**MR1916** is a potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor developed following chemical optimization efforts[2][3]. MR1916 displays strong inhibitory activity against PDE10A in humans, rats, and monkeys, with IC50 values less than 0.1 nM and >1,000-fold selectivity over other phosphodiesterases[2][3]. It has excellent brain penetration and bioavailability[2][3], and is orally active in preclinical studies. Its mechanisms involve elevation of intracellular cAMP and cGMP via PDE10A inhibition, impacting neuronal signaling in the brain, particularly in striatal medium spiny neurons. MR1916 shows promise as a therapeutic candidate for several CNS disorders, including: - L-dopa-induced dyskinesia (LID) in Parkinson's disease, where it reduces dyskinesia severity in primate models and exhibits a favorable side-effect profile compared to existing drugs like amantadine[2][7][8]. - Enhancement of antipsychotic effects and cognitive performance, as shown in combination studies with risperidone[3][5]. - Reduction of alcohol self-administration in animal models, likely due to modulating striatal neuronal activation and gene expression (Egr1, Fos, FosB, ΔFosB, Drd1, Drd2, Pde10a, Penk, Tac1)[1][9]. - Safety and tolerability trials in healthy subjects have been initiated, primarily in the context of schizophrenia therapy[6].