The PDE10A enzyme is expressed primarily in the brain, mostly in the striatum, nucleus accumbens and olfactory tubercle, and is thought to be particularly important in regulating the activity of dopamine-sensitive medium spiny neurons in the striatum which are known to be targets of conventional antipsychotic drugs.[2] Older PDE10A inhibitors such as papaverine have been shown to produce antipsychotic effects in animal models,[3] and more potent and selective PDE10A inhibitors are a current area of research for novel antipsychotic drugs which act through a different pathway to conventional dopamine or 5-HT2A antagonist drugs and may have a more favourable side effects profile.[4]
Mardepodect is currently one of the furthest advanced PDE10A inhibitors in development and has progressed through to Phase II clinical trials in humans.[5] In 2017, development of mardepodect for the treatment of schizophrenia and Huntington's disease was discontinued.[6]
^Verhoest PR, Chapin DS, Corman M, Fonseca K, Harms JF, Hou X, et al. (August 2009). "Discovery of a novel class of phosphodiesterase 10A inhibitors and identification of clinical candidate 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the treatment of schizophrenia". Journal of Medicinal Chemistry. 52 (16): 5188–96. doi:10.1021/jm900521k. PMID19630403.
^CA 2673435 C, Vorhoest, Patrick Robert & Proulx, Caroline, "Succinate salt of 2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl) phenoxy)methyl)quinoline", published 2008-07-17
^Siuciak JA, Chapin DS, Harms JF, Lebel LA, McCarthy SA, Chambers L, et al. (August 2006). "Inhibition of the striatum-enriched phosphodiesterase PDE10A: a novel approach to the treatment of psychosis". Neuropharmacology. 51 (2): 386–96. doi:10.1016/j.neuropharm.2006.04.013. PMID16780899. S2CID13447370.
