Cyclic–Nucleotide Phosphodiesterases in the Central Nervous System: From Biology to Drug Discovery

Methods and advances for understanding phosphodiesterases (PDEs), a hot area of drug and therapeutic research Cyclic–nucleotide phosphodiesterases (PDEs) are critical for the regulation of processes from cell birth to cell death, but diseases of the central nervous system (CNS) often disrupt these essential functions. Cyclic–Nucleotide Phosphodiesterases in the Central Nervous System: From Biology to Drug Discovery helps scientists understand the concepts to develop more selective and potent inhibitors and modulators as treatments for neurological diseases. A number of expert authors from both academia and industry capture these principles by focusing on the areas of greatest scientific and medical interest. While explaining the science behind PDEs, this book provides readers with: Analytical tools for translating biological knowledge and developing inhibitors and modulators of PDE The expertise of leading researchers from both basic and applied sciences Discussion about PDE biology and enzymology with respect to the brain and spinal cord Knowledge for developing treatments for specific CNS diseases like schizophrenia, Alzheimers, Parkinsons, depression, and spinal cord injuries Information about drug discovery tools, such as in vitro assays and X–ray structures, for medicinal chemistry As a comprehensive and advanced guide that applies to both academic and industry research, this book helps readers discover strategies and insights into PDE biology and chemistry, therapeutic approaches and opportunities, and novel medicines.

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

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 Parkinsons disease and Huntingtons disease.