Edelinontrine

There are currently limited effective treatments available to improve lusitropy in patients suffering from heart failure with preserved ejection fraction. The role of PDE9A in diastolic dysfunction has been well-studied over recent years, with a special focus on its association with myocardial hypertrophy. Recent insights into PDE9A inhibition have brought to light the potential for reversal of cardiac remodeling, with multiple studies showing promising results in preclinical data.

This expert opinion provides an overview of the role of PDE9A in diastolic heart dysfunction along with the efficacy of PDE9A inhibitors in laboratory models of heart failure with preserved ejection fraction.

The available data on PDE9A inhibition in preclinical studies suggest that there is potential for reversal of diastolic dysfunction and myocardial hypertrophy, however, conflicting data suggests that further studies are required before progressing to clinical trials.

The growing interest on the therapeutic potential against neurodegeneration of Cannabis sativa extracts, and of phytocannabinoids in particular, is paralleled by a limited understanding of the undergoing biochemical pathways in which these natural compounds may be involved. Computational tools are nowadays commonly enrolled in the drug discovery workflow and can guide the investigation of macromolecular targets for such molecules. In this contribution, in silico techniques have been applied to the study of C. sativa constituents at various extents, and a total of seven phytocannabinoids and four terpenes were considered. On the side of ligand‐based virtual screening, physico‐chemical descriptors were computed and evaluated, highlighting the phytocannabinoids possessing suitable drug‐like properties to potentially target the central nervous system. Our previous findings and literature data prompted us to investigate the interaction of these molecules with phosphodiesterases (PDEs), a family of enzymes being studied for the development of therapeutic agents against neurodegeneration. Among the compounds, structure‐based techniques such as docking and molecular dynamics (MD), highlighted cannabidiol (CBD) as a potential and selective PDE9 ligand, since a promising calculated binding energy value (−9.1 kcal/mol) and a stable interaction in the MD simulation timeframe were predicted.Additionally, PDE9 inhibition assay confirmed the computational results, and showed that CBD inhibits the enzyme in the nanomolar range in vitro, paving the way for further development of this phytocannabinoid as a therapeutic option against neurodegeneration.