Abstract
Activation of the adenylyl cyclase – PKA – CREB signaling pathway has been shown to be critical for learning and the creation and consolidation of memory. The PDE4, or cAMP-specific, phosphodiesterases (PDEs) are important modulators of cAMP levels in the central nervous system. The establishment of the essential role of PDE4 isoforms in learning and memory has been based on a long-standing interplay between experiments in genetically-tractable organisms, such as flies and mice, and pharmacological studies in rodents, primates and humans. Collectively, these diverse approaches have demonstrated the pivotal role of PDE4s in learning and memory and that pharmacological targeting of PDE4s can enhance learning, memory and cognition in humans. However, several challenges remain before PDE4 inhibitors can be used clinically in disorders of cognition and memory. Current priorities in PDE4 drug discovery focused on the CNS include 1) further refinement of isoform selectivity; 2) more precise action at CNS targets implicated in cognition and memory, such as those in forebrain and hippocampus, while reducing undesired action at other CNS (area postrema) and non-CNS targets (CFTR, gastric acid secretion) that account for the limiting side effects of many, but not all, PDE4 inhibitors in clinical trials; and 3) improved pharmacokinetics and dosing.
Keywords
Roflumilast, Apremilast, Zatolmilast, Nerandomilast, Orismilast