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

Chong Zhang,Mark E Gurney,Ying Xu,Han-Ting Zhang,Mingxin Yang,Benjamin D Auerbach,James M O’Donnell,Gaowen Li,Richard J Salvi,David Fox,Anirudh Chowdhary

doi:10.1038/s41386-018-0178-6

Abstract

Inhibitors of phosphodiesterase-4 (PDE4) have beneficial effects on memory in preclinical and clinical studies. Development of these drugs has stalled due to dose-limiting side effects of nausea and emesis. While use of subtype-selective inhibitors (i.e., for PDE4A, B, or D) could overcome this issue, conservation of the catalytic region, to which classical inhibitors bind, limits this approach. The present study examined the effects of BPN14770, an allosteric inhibitor of PDE4D, which binds to a primate-specific, N-terminal region. In mice engineered to express PDE4D with this primate-specific sequence, BPN14770 was 100-fold more potent for improving memory than in wild-type mice; meanwhile, it exhibited low potency in a mouse surrogate model for emesis. BPN14770 also antagonized the amnesic effects of scopolamine, increased cAMP signaling in brain, and increased BDNF and markers of neuronal plasticity associated with memory. These data establish a relationship between PDE4D target engagement and effects on memory for BPN14770 and suggest clinical potential for PDE4D-selective inhibitors.

Highlights

Genetic studies in model organisms and recent use of exon sequencing in rare human disorders identify the cyclic adenosine monophosphate (AMP)–protein kinase A (PKA)–cyclic AMP (cAMP)-response element binding protein (CREB) pathway as fundamental to early and late stages of memory formation [1]
Calcium/ calmodulin-dependent adenylyl cyclase acts downstream of the N-methyl-D-aspartate (NMDA) receptor to trigger cAMP synthesis in response to calcium influx [5]. This activates the PKA–CREB pathway which is responsible for the earliest, transient stages of memory such as long-term potentiation (LTP) in the hippocampus [6] and changes in protein synthesis and gene expression that lead to memory consolidation [7], increased expression of brainderived neurotrophic factor [8], and neurogenesis [9, 10]
The core amino acid sequence of PDE4D7 from UCR1 through the end of the catalytic domain is absolutely conserved across all species except for the phenylalanine in UCR2 unique to primate which in non-primate species is a tyrosine (Fig. 1a, b)

Summary

Introduction

Genetic studies in model organisms and recent use of exon sequencing in rare human disorders identify the cyclic AMP (cAMP)–protein kinase A (PKA)–cAMP-response element binding protein (CREB) pathway as fundamental to early and late stages of memory formation [1]. Calcium/ calmodulin-dependent adenylyl cyclase acts downstream of the N-methyl-D-aspartate (NMDA) receptor to trigger cAMP synthesis in response to calcium influx [5]. This activates the PKA–CREB pathway which is responsible for the earliest, transient stages of memory such as long-term potentiation (LTP) in the hippocampus [6] and changes in protein synthesis and gene expression that lead to memory consolidation [7], increased expression of brainderived neurotrophic factor [8], and neurogenesis [9, 10]. PDE4D enzymatic activity is dynamically regulated by signaling through the PKA–CREB pathway in a manner critical to normal cognitive function

Methods

Results

Conclusion