PDE10A Inhibitors-Clinical Failure or Window Into Antipsychotic Drug Action?

摘要: PDE10A, a phosphodiesterase that inactivates both cAMP and cGMP, is unique signaling molecule in being highly nearly exclusively expressed striatal medium spiny neurons. These neurons dynamically integrate cortical information with dopamine-signaled value to mediate action selection among available behavioral options. Medium are components of either the direct or indirect output pathways. Selective activation pathway by dopamine D2 receptor antagonists putatively key element mechanism their antipsychotic efficacy. While PDE10A all neurons, studies rodents indicated inhibition has effects several assays phenocopy inhibition. This finding gave rise hypothesis also preferentially activates consistent electrophysiological, neurochemical, molecular inhibitors. data underwrote industry-wide efforts investigate develop inhibitors as novel antipsychotics. Disappointingly, from 3 companies failed evidence activity patients schizophrenia same extent standard-of-care antagonists. Given notable similarities between antagonists, gaining an understanding why only latter class affords window into basis for this therapeutic With mind, we review on step toward back-translating limited efficacy inhibitors, hopefully inform new better therapeutics treat psychosis schizophrenia.