New and emerging directions in pharmaceutical research to better treat schizophrenia

Although the dopamine hypothesis has been the cornerstone of schizophrenia therapeutics, it is clear that dopamine-based approaches do not treat all aspects of the disease. Moreover, many schizophrenia patients fail to respond to current antipsychotics. Integrating chemistry, biology, and pharmacology, this book explores emerging directions in pharmaceutical research for drug targeting and discovery in order to find more effective treatments for schizophrenia, one of the most serious and widespread psychiatric diseases.

Targets and Emerging Therapies for Schizophrenia presents the basics of schizophrenia, drug targets for the disease, and potential new drugs and therapeutics. It begins with a discussion of prevalence and etiology. Then, it describes therapies such as dopamine agonists and phosphodiesterase (PDE) inhibitors as well as growing research aimed at addressing untreated symptoms. Next, the authors discuss receptor modulators, inhibitors, and targeting strategies for drug discovery. Both the neurobiological and chemical aspects of all major pharmacological targets are examined.

With contributions from an international team of pioneering pharmaceutical researchers, this book compiles the current knowledge in the field, setting the stage for new breakthroughs in the treatment of schizophrenia.Targets and Emerging Therapies for Schizophrenia:

WithTargets and Emerging Therapies for Schizophrenia as their guide, drug discovery and development scientists have the information they need to advance their own research so that new, more effective treatments for schizophrenia will soon be a reality.

JEFFREY S. ALBERT, PhD, is a Project Leader and Head of Lead Generation Chemistry in AstraZeneca's neuroscience department. He has authored or coauthored more than forty publications, mostly focusing on novel therapeutic targets involved in depression, schizophrenia, and Alzheimer's disease and on the development and application of fragment-based lead generation methodologies.

MICHAEL W. WOOD, PhD, is an External Collaborations Director in AstraZeneca's neuroscience unit where he is responsible for coordinating research to deliver novel therapeutics targeting schizophrenia as well as other neuroscience treatments. He has been focused on neuroscience drug discovery research for fifteen years.

Preface vii

Contributors xi

Introduction 1
Alan J. Cross

1 Dopaminergic Hypothesis of Schizophrenia: A Historical Perspective 5
Aurelija Jucaite and Svante Nyberg

2 Dopamine D2/D3 Partial Agonists as Antipsychotics 37
Philip G. Strange

3 D1/D5 Dopamine Agonists as Pharmacotherapy for Schizophrenia 51
Kevin N. Boyd and Richard B. Mailman

4 Phosphodiesterase Inhibitors as a Novel Therapeutic Approach for Schizophrenia 85
Judith A. Siuciak and William J. Pitts

5 Glutamatergic Synaptic Dysregulation in Schizophrenia 115
Joseph T. Coyle, Alo Basu, and Michael Benneyworth

6 Metabotropic Glutamate 2/3 Receptor Agonists and Positive Allosteric Modulators of Metabotropic Glutamate Receptor 2 as Novel Agents for the Treatment of Schizophrenia 143
Gerard J. Marek, Bruce J. Kinon, David L. McKinzie, Jeffrey M. Schkeryantz, and James A. Monn

7 AMPA Receptor Positive Modulators 187
John A. Morrow, John K.F. Maclean, and Craig Jamieson

8 Progress in the Exploration and Development of GlyT1 Inhibitors for Schizophrenia 233
Jeffrey S. Albert and Michael W. Wood

9 Combined Dopamine D2 and 5-Hydroxytryptamine (5-HT)1A Receptor Strategies for the Treatment of Schizophrenia: A Pharmacological and Chemical Perspective 255
Andrew C. McCreary, Roelof W. Feenstra, and Caitlin A. Jones

10 5-HT2C and 5-HT6 Receptor Targeted Emerging Approaches in Schizophrenia 273
Sharon Rosenzweig-Lipson, John Dunlop, Lee E. Schechter, Thomas A. Comery, Jonathan Gross, and Karen L. Marquis

11 The Cholinergic Hypothesis: An Introduction to the Hypothesis and a Short History 295
Joseph I. Friedman, Isabella Kanellopoulou, and Vladan Novakovic

12 7 Nicotinic Acetylcholine Receptors in the Treatment of Schizophrenia 319
Mihály Hajós and Bruce N. Rogers

13 Muscarinic Acetylcholine Receptors as Novel Targets for the Development of Therapeutics for Schizophrenia 355
Christian C. Felder, David L. McKinzie, Richard C. Thompson, and Bin Liu

14 Will Modulation of Neuropeptide Receptors Produce the Next Generation of Antipsychotic Drugs? A Focus on the Neurokinin and Neurotensin Systems 381
Lee A. Dawson, Paul W. Smith, and Jeannette M. Watson

15 GABA and Schizophrenia 425
John H. Kehne and George D. Maynard

Index 469