Comparison of the Pharmacological Profiles of Selective PDE4B and PDE4D Inhibitors in the Central Nervous System

Abstract

Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase 4 (PDE4) has been proposed as a potential treatment for a series of neuropsychological conditions such as depression, anxiety and memory loss. However, the specific involvement of each of the PDE4 subtypes (PDE4A, 4B and 4C) in different categories of behavior has yet to be elucidated. In the present study, we compared the possible pharmacological effects of PDE4B and PDE4D selective inhibitors, A-33 and D159687, in mediating neurological function in mice. Both compounds were equally potent in stimulating cAMP signaling in the mouse hippocampal cell line HT-22 leading to an increase in CREB phosphorylation. In contrast, A-33 and D159687 displayed distinct neuropharmacological effects in mouse behavioral tests. A-33 has an antidepressant-like profile as indicated by reduced immobility time in the forced swim and tail suspension tasks, as well as reduced latency to feed in the novelty suppressed feeding test. D159687, on the other hand, had a procognitive profile as it improved memory in the novel object recognition test but had no antidepressant or anxiolytic benefit. The present data suggests that inhibitors targeting specific subtypes of PDE4 may exhibit differential pharmacological effects and aid a more efficient pharmacotherapy towards neuropsychological conditions.

Memory enhancing effects of BPN14770, an allosteric inhibitor of phosphodiesterase-4D, in wild-type and humanized mice

“…Saturation binding of [ 3 H]-rolipram has been used to quantify PDE4 binding sites in mouse brain membrane fractions [ 30 ]. Since rolipram has little selectivity for PDE4 subtypes, total binding should represent the sum of binding to PDE4A, B, and D, the primary PDE4 subtypes expressed in brain [ 39 , 40 ]. [ 3 H]-rolipram bound with high affinity to membranes prepared from brains of wild-type ( K d = 3.84 nM) and humanized PDE4D ( K d = 3.72 nM) mice (Fig.…”

“…Mice were treated with various doses of BPN14770 or vehicle and killed 1 h after dosing by rapid decapitation, and brains were immediately dissected on ice, flash frozen in liquid nitrogen, and stored at −80 °C. On the day of assay, frozen brain samples were analyzed using the cAMP complete ELISA kit (Enzo Life Sciences, Farmingdale, NY) according to the assay protocol [ 34 ].…”

Genome-wide Association Study of Anxiety and Stress-related Disorders in the iPSYCH Cohort

“…Additionally, pharmacological profiles of selective PDE4B inhibitors have demonstrated clear antidepressant and anxiolytic benefits 37 .…”

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

“…[25,26]. This already allows more specificity between functional effects, in this particular case to distinguish between affect (PDE4B) and cognition (PDE4D) [27]. However, to our knowledge none of available PDE inhibitors is selective at the level of PDE isoform variants (e.g.…”