TY - JOUR
T1 - Memory enhancing effects of BPN14770, an allosteric inhibitor of phosphodiesterase-4D, in wild-type and humanized mice
AU - Zhang, Chong
AU - Xu, Ying
AU - Chowdhary, Anirudh
AU - Fox, David
AU - Gurney, Mark E.
AU - Zhang, Han Ting
AU - Auerbach, Benjamin D.
AU - Salvi, Richard J.
AU - Yang, Mingxin
AU - Li, Gaowen
AU - O’Donnell, James M.
N1 - Funding Information:
CZ designed, conducted, and analyzed the experiments with oversight by YX, JMO’D, and MEG. AC performed the PDE4 enzyme inhibition assays. DF conducted the X-ray crystallography studies. CZ, BDA and RJS performed electrophysiological recordings. CZ and MEG provided the humanized PDE4D mice, contributed to the statistical analysis, and co-wrote the manuscript. CZ and YX contributed equally to this manuscript. This work was supported by a research grant from the National Institutes of Health Blueprint Neurotherapeutics Program through the National Institute of Neurological Disorders and Stroke and the National Institute on Aging (grant number NS078034) to MEG with a sub-award to YX and independently by Tetra Discovery Partners, Inc. MEG is an employee of Tetra Discovery Partners, Inc. which has a financial interest in BPN14770.
Publisher Copyright:
© 2018, The Author(s).
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2018/10/1
Y1 - 2018/10/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41386-018-0178-6
DO - 10.1038/s41386-018-0178-6
M3 - Article
C2 - 30131563
AN - SCOPUS:85052328208
SN - 0893-133X
VL - 43
SP - 2299
EP - 2309
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 11
ER -