Disturbances of the basal ganglia processes is heavily involved in schizophrenia. Phosphodiesterase 10A (PDE10A) is a basal ganglia specific hydrolase, which plays an essential role in regulating cAMP/PKA and cGMP/PKG signalling cascades by controlling the magnitude, duration and cellular location of cAMP/cGMP elevation. Biochemical and behavioral data indicate that PDE10A inhibition activates cAMP/PKA signalling in the basal ganglia, leading to the potentiation of dopamine D₁ receptor signalling, and concomitant inhibition of dopamine D₂ receptor signalling. Preclinical evidence in a range of animal models suggests that a PDE10A inhibitor could provide efficacy on positive, cognitive and negative symptoms of schizophrenia and PDE10A inhibitors are currently being evaluated in clinical trials for the treatment of schizophrenia.

Importance of the field: PDE10A inhibition has generated much excitement as a potential novel mechanism for the treatment of the positive symptoms of schizophrenia. PDE10A is only ‘10 years old’ as a drug discovery target since it was first discovered in 1999, and thus PDE10A is an example of the modern drug discovery paradigm demonstrating the highly increased speed by which novel targets can be validated, hits identified, lead-optimization performed and compounds progressed into clinical trials. At least one PDE10A inhibitor compound has been progressed to clinical Phase II for the treatment of schizophrenia. And preclinical evidence suggests that a PDE10A inhibitor could provide antipsychotic, pro-cognitive and negative symptom efficacy in the same dose range.Areas covered in this review: The review surveys advances in the medicinal chemistry of PDE10A through the patent literature since 2007. The article is supplemented with selected publications from the scientific literature.What the reader will gai...

(2013). Phosphodiesterase 10A inhibitors: a 2009 – 2012 patent update. Expert Opinion on Therapeutic Patents: Vol. 23, No. 1, pp. 31-45. doi: 10.1517/13543776.2012.739157

The recent resurgence of classical psychedelic compounds, specifically 5-HT _2A receptor agonists, as potential therapeutics has led to numerous initiatives aimed at better understanding the mechanisms underlying their effects. Psychedelic compounds are commonly known as hallucinogens. One of the major outstanding questions in the field is whether altered states of consciousness—the hallucinogenic or psychedelic experience—is a prerequisite for the therapeutic effect. As a result, several academic and commercial efforts are focused on developing 5-HT _2A receptor agonists that are speculated not to have these consciousness-altering effects. However, these efforts largely rely on chemical analogs of supposedly non-hallucinogenic 5-HT _2A receptor agonists, such as lisuride and ergotamine. Our review of the literature indicates that there is no basis for claiming that lisuride or ergotamine are non-hallucinogenic at relevant concentrations in the brain. This does not invalidate current efforts to produce non-hallucinogenic 5-HT _2A receptor agonists for the potential benefit of patients, but it calls for caution in the reliance on animal data in the pursuit of such compounds and highlights the need for rigorous determination of target engagement in humans before claiming that 5-HT _2A receptor agonists are non-hallucinogenic.