Cyclic-Nucleotide Phosphodiesterases in the Central Nervous System

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.

• PREFACE viiCONTRIBUTORS ix1 PHOSPHODIESTERASES AND CYCLIC NUCLEOTIDE SIGNALING IN THE CNS 1Marco Conti and Wito Richter2 PUTTING TOGETHER THE PIECES OF PHOSPHODIESTERASE DISTRIBUTION PATTERNS IN THE BRAIN: A JIGSAW PUZZLE OF CYCLIC NUCLEOTIDE REGULATION 47Michy P. Kelly3 COMPARTMENTALIZATION AND REGULATION OF CYCLIC NUCLEOTIDE SIGNALING IN THE CNS 59Manuela Zaccolo and Alessandra Stangherlin4 PHARMACOLOGICAL MANIPULATION OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASE SIGNALING FOR THE TREATMENT OF NEUROLOGICAL AND PSYCHIATRIC DISORDERS IN THE BRAIN 77Frank S. Menniti, Niels Plath, Niels Svenstrup, and Christopher J. Schmidt5 RECENT RESULTS IN PHOSPHODIESTERASE INHIBITOR DEVELOPMENT AND CNS APPLICATIONS 115David P. Rotella6 CRYSTAL STRUCTURES OF PHOSPHODIESTERASES AND IMPLICATION ON DISCOVERY OF INHIBITORS 145Hengming Ke, Huanchen Wang, Mengchun Ye, and Yingchun Huang7 INHIBITION OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASES TO REGULATE MEMORY 171Han-Ting Zhang, Ying Xu, and James O’Donnell8 EMERGING ROLE FOR PDE4 IN NEUROPSYCHIATRIC DISORDERS: TRANSLATING ADVANCES FROM GENETIC STUDIES INTO RELEVANT THERAPEUTIC STRATEGIES 211Sandra P. Zoubovsky, Nicholas J. Brandon, and Akira Sawa9 BEYOND ERECTILE DYSFUNCTION: UNDERSTANDING PDE5 ACTIVITY IN THE CENTRAL NERVOUS SYSTEM 223Eva P.P. Bollen, Kris Rutten, Olga A.H. Reneerkens, Harry M.W. Steinbusch, and Jos Prickaerts10 MOLECULAR AND CELLULAR UNDERSTANDING OF PDE10A: A DUAL-SUBSTRATE PHOSPHODIESTERASE WITH THERAPEUTIC POTENTIAL TO MODULATE BASAL GANGLIA FUNCTION 247Erik I. Charych and Nicholas J. Brandon11 ROLE OF CYCLIC NUCLEOTIDE SIGNALING AND PHOSPHODIESTERASE ACTIVATION IN THEMODULATION OF ELECTROPHYSIOLOGICAL ACTIVITY OF CENTRAL NEURONS 269Sarah Threlfell and Anthony R. West12 THE ROLE OF PHOSPHODIESTERASES IN DOPAMINE SYSTEMS GOVERNING MOTIVATED BEHAVIOR 303Gretchen L. Snyder, Joseph P. Hendrick, and Akinori Nishi13 INHIBITION OF PHOSPHODIESTERASES AS A STRATEGY FOR TREATMENT OF SPINAL CORD INJURY 353Elena Nikulina and Marie T. FilbinINDEX 375