Cyclic-Nucleotide Phosphodiesterases in the Central Nervous System

This book reviews advances in understanding phosphodiesterases
within the central nervous system and their therapeutic
applications. A range of expert authors from both academia and
industry describe these, then focus on the areas of greatest
scientific and medical interest to provide more detailed coverage.
Therapeutic and drug discovery applications are covered for
diseases including Alzheimer's, Parkinson's, schizophrenia,
erectile dysfunction, and spinal cord injuries. There is also a
chapter on drug discovery tools such as in vitro assays and X-ray
structures for medicinal chemistry studies.

Autorentext

NICHOLAS BRANDON works at AstraZeneca within the
Neuroscience Innovative Medicines Group. He has spent his career in
drug discovery with a strong interest in developing
phosphodiesterase inhibitors for neuropsychiatric disorders and
understanding the basic mechanisms of phosphodiesterase
function.

ANTHONY WEST is an Associate Professor in the Department
of Neuroscience at Rosalind Franklin University. He has studied PDE
function in the basal ganglia for over fifteen years, focusing on
neurochemical and electrophysiological changes induced by PDE
inhibitors in the healthy brain and in animal models of
Parkinson's disease and Huntington's disease.

Zusammenfassung
This book reviews advances in understanding phosphodiesterases within the central nervous system and their therapeutic applications. A range of expert authors from both academia and industry describe these, then focus on the areas of greatest scientific and medical interest to provide more detailed coverage. Therapeutic and drug discovery applications are covered for diseases including Alzheimer's, Parkinson's, schizophrenia, erectile dysfunction, and spinal cord injuries. There is also a chapter on drug discovery tools such as in vitro assays and X-ray structures for medicinal chemistry studies.

Inhalt

PREFACE vii

CONTRIBUTORS ix

1 PHOSPHODIESTERASES AND CYCLIC NUCLEOTIDE SIGNALING IN THE
CNS 1

Marco Conti and Wito Richter

2 PUTTING TOGETHER THE PIECES OF PHOSPHODIESTERASE
DISTRIBUTION PATTERNS IN THE BRAIN: A JIGSAW PUZZLE OF CYCLIC
NUCLEOTIDE REGULATION 47

Michy P. Kelly

3 COMPARTMENTALIZATION AND REGULATION OF CYCLIC NUCLEOTIDE
SIGNALING IN THE CNS 59

Manuela Zaccolo and Alessandra Stangherlin

4 PHARMACOLOGICAL MANIPULATION OF CYCLIC NUCLEOTIDE
PHOSPHODIESTERASE SIGNALING FOR THE TREATMENT OF NEUROLOGICAL AND
PSYCHIATRIC DISORDERS IN THE BRAIN 77

Frank S. Menniti, Niels Plath, Niels Svenstrup, and Christopher
J. Schmidt

5 RECENT RESULTS IN PHOSPHODIESTERASE INHIBITOR DEVELOPMENT
AND CNS APPLICATIONS 115

David P. Rotella

6 CRYSTAL STRUCTURES OF PHOSPHODIESTERASES AND IMPLICATION ON
DISCOVERY OF INHIBITORS 145

Hengming Ke, Huanchen Wang, Mengchun Ye, and Yingchun
Huang

7 INHIBITION OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASES TO
REGULATE MEMORY 171

Han-Ting Zhang, Ying Xu, and James O'Donnell

8 EMERGING ROLE FOR PDE4 IN NEUROPSYCHIATRIC DISORDERS:
TRANSLATING ADVANCES FROM GENETIC STUDIES INTO RELEVANT THERAPEUTIC
STRATEGIES 211

Sandra P. Zoubovsky, Nicholas J. Brandon, and Akira Sawa

9 BEYOND ERECTILE DYSFUNCTION: UNDERSTANDING PDE5 ACTIVITY IN
THE CENTRAL NERVOUS SYSTEM 223

Eva P.P. Bollen, Kris Rutten, Olga A.H. Reneerkens, Harry M.W.
Steinbusch, and Jos Prickaerts

10 MOLECULAR AND CELLULAR UNDERSTANDING OF PDE10A: A
DUAL-SUBSTRATE PHOSPHODIESTERASE WITH THERAPEUTIC POTENTIAL TO
MODULATE BASAL GANGLIA FUNCTION 247

Erik I. Charych and Nicholas J. Brandon

11 ROLE OF CYCLIC NUCLEOTIDE SIGNALING AND PHOSPHODIESTERASE
ACTIVATION IN THE

MODULATION OF ELECTROPHYSIOLOGICAL ACTIVITY OF CENTRAL NEURONS
269

Sarah Threlfell and Anthony R. West

12 THE ROLE OF PHOSPHODIESTERASES IN DOPAMINE SYSTEMS
GOVERNING MOTIVATED BEHAVIOR 303

Gretchen L. Snyder, Joseph P. Hendrick, and Akinori
Nishi

13 INHIBITION OF PHOSPHODIESTERASES AS A STRATEGY FOR
TREATMENT OF SPINAL CORD INJURY 353

Elena Nikulina and Marie T. Filbin

INDEX 375