The Novel Phosphodiesterase 9A Inhibitor BI 409306 Increases Cyclic Guanosine Monophosphate Levels in the Brain, Promotes Synaptic Plasticity, and Enhances Memory Function in Rodents.

N-methyl-d-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) is an established cellular model underlying learning and memory, and involves intracellular signaling mediated by the second messenger cyclic guanosine monophosphate (cGMP). As phosphodiesterase (PDE)9A selectively hydrolyses cGMP in areas of the brain related to cognition, PDE9A inhibitors may improve cognitive function by enhancing NMDA receptor-dependent LTP. This study aimed to pharmacologically characterize BI 409306, a novel PDE9A inhibitor, using in vitro assays and in vivo determination of cGMP levels in the brain. Further, the effects of BI 409306 on synaptic plasticity evaluated by LTP in ex vivo hippocampal slices and on cognitive performance in rodents were also investigated. In vitro assays demonstrated that BI 409306 is a potent and selective inhibitor of human and rat PDE9A with mean concentrations at half-maximal inhibition (IC50) of 65 and 168 nM. BI 409306 increased cGMP levels in rat prefrontal cortex and cerebrospinal fluid and attenuated a reduction in mouse striatum cGMP induced by the NMDA-receptor antagonist MK-801. In ex vivo rat brain slices, BI 409306 enhanced LTP induced by both weak and strong tetanic stimulation. Treatment of mice with BI 409306 reversed MK-801-induced working memory deficits in a T-maze spontaneous-alternation task and improved long-term memory in an object recognition task. These findings suggest that BI 409306 is a potent and selective inhibitor of PDE9A. BI 409306 shows target engagement by increasing cGMP levels in brain, facilitates synaptic plasticity as demonstrated by enhancement of hippocampal LTP, and improves episodic and working memory function in rodents. SIGNIFICANCE STATEMENT: This preclinical study demonstrates that BI 409306 is a potent and selective PDE9A inhibitor in rodents. Treatment with BI 409306 increased brain cGMP levels, promoted long-term potentiation, and improved episodic and working memory performance in rodents. These findings support a role for PDE9A in synaptic plasticity and cognition. The potential benefits of BI 409306 are currently being investigated in clinical trials

Effects of GPR139 agonism on effort expenditure for food reward in rodent models: Evidence for pro-motivational actions

Apathy, deficiency of motivation including willingness to exert effort for reward, is a common symptom in many psychiatric and neurological disorders, including depression and schizophrenia. Despite improved understanding of the neurocircuitry and neurochemistry underlying normal and deficient motivation, there is still no approved pharmacological treatment for such a deficiency. GPR139 is an orphan G protein-coupled receptor expressed in brain regions which contribute to the neural circuitry that controls motivation including effortful responding for reward, typically sweet gustatory reward. The GPR139 agonist TAK-041 is currently under development for treatment of negative symptoms in schizophrenia which include apathy. To date, however, there are no published preclinical data regarding its potential effect on reward motivation or deficiencies thereof. Here we report in vitro evidence confirming that TAK-041 increases intracellular Ca2+ mobilization and has high selectivity for GPR139. In vivo, TAK-041 was brain penetrant and showed a favorable pharmacokinetic profile. It was without effect on extracellular dopamine concentration in the nucleus accumbens. In addition, TAK-041 did not alter the effort exerted to obtain sweet gustatory reward in rats that were moderately food deprived. By contrast, TAK-041 increased the effort exerted to obtain sweet gustatory reward in mice that were only minimally food deprived; furthermore, this effect of TAK-041 occurred both in control mice and in mice in which deficient effortful responding was induced by chronic social stress. Overall, this study provides preclinical evidence in support of GPR139 agonism as a molecular target mechanism for treatment of apathy