The Use of PDE10A and PDE9 Inhibitors for Treating Schizophrenia

Abstract

Schizophrenia (Scz) is a chronic and debilitating neurological disorder that afflicts approximately 1% of the general population with an increased incidence within families. Signs of this disorder typically appear between the ages of 16-30 although rare cases of childhood (<13) onset exist. Diagnosis of scz requires symptoms that persist for a duration of 1 month over a 6-month time period. The broad spectrum of symptoms are typically split into three categories: positive, negative, and cognitive. Implicit within these categories is the difficulty for stand-alone treatment methods, suggesting a combination of pharmacological and psychological treatment strategies is needed to manage this disease. Furthermore, while current pharmaceuticals are moderately effective at managing positive symptoms, the severe side effects lower patient compliance. Additionally, drugs used to treat negative and cognitive symptoms only have modest benefits, at best. Due to these limitations, there is a clear need for novel pharmaceuticals that modulate dysfunctional neurological pathways in scz patients. As such, both academic and pharmaceutical researchers are focused on identifying enzymes that can attenuate neurological signaling in disease-relevant brain regions. Specifically, this chapter will provide an in-depth review of current drug discovery efforts focused on inhibiting phosphodiesterase 10 and 9 (PDE10A, PDE9A, respectively).

Highlight of New Phosphodiesterase 10A Inhibitors Using Molecular Docking

“…The compound a is one of the best PDE 10A inhibitors (Tuttle and Kormos, 2014). Its experimental IC 50 value is 0.4 nM.…”

“…Molecular docking calculations were undertaken using the last version of AutoDock (Morris et al, 1998). The compound a is one of the best PDE 10A inhibitors (Tuttle and Kormos, 2014) with a value of IC 50 of 0.4 nM. This compound was taken as starting structure for search of similar compounds.…”

A Novel Role of Cyclic Nucleotide Phosphodiesterase 10A in Pathological Cardiac Remodeling and Dysfunction

“…In addition, ISO-and PE-induced hypertrophy was partially attenuated by TP-10 (Supplemental Figure S5C-D). TP-10 inhibits PDE10A activity at IC 50 0.3nM in test tubes, with at least 2500-fold selectivity for PDE10A over other PDEs [24][25][26] . However, TP-10 is highly protein bound once introduced in the culture medium, and thus higher doses of TP-10 are often needed 25,27 .…”

Radiosynthesis and biological evaluation of the new PDE10A radioligand [18F]AQ28A

“…Thus, inhibition of PDE10A has effects similar to those of D 2 antagonists and D 1 agonists regarding cyclic nucleotide levels . In contrast to selective D 2 antagonists and D 1 agonists, PDE10A inhibitors activate both pathways equally and thereby provide a unique potential to treat diseases linked to striatal dysfunction such as schizophrenia, Huntington disease, or obsessive compulsive disorder. Significant understanding of the biological role of PDE10A as achievable by positron emission tomography (PET) would support the development of new therapeutic strategies.…”