QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.108.143420v1 329/2/404    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Enna, S. J. Articles by Williams, M. Search for Related Content PubMed PubMed Citation Articles by Enna, S. J. Articles by Williams, M.

PERSPECTIVES IN PHARMACOLOGY

Challenges in the Search for Drugs to Treat Central Nervous System Disorders

Department of Molecular and Integrative Physiology and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (S.J.E.); Discovery Research, Cephalon, Inc., West Chester, Pennsylvania (M.W.); and Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, Illinois (M.W.)

The history of drug discovery spans approximately 200,000 years. For much of this time, the identification of therapeutic agents was empirical, with the shift to a more hypothesis-driven approach occurring in the late 19th century. Since then, the objective has changed from identifying an active drug and its mechanism of action to determining therapeutic potential only after identifying drug-like compounds that interact with a target site. Although the emphasis on target identification, or "targephilia," has yielded novel drugs, overall it appears to have slowed the drug discovery process, especially for compounds used in treating central nervous system (CNS) disorders. This is because the "targephilic" approach requires a good understanding of target physiology and its integration with the target organ, with a hierarchical integration from in vitro cellular and functional tissue studies to animal models that reasonably predict human responses. Because the majority of CNS drugs were discovered empirically, drug discovery in this area appears less amenable to target-based approaches than it seems for other types of therapeutics. Improving the success rate in CNS drug discovery requires a more pharmacometric-based approach, with a renewed emphasis on defining basic CNS function in intact animals and a more systematic in vivo screening of novel structures. Efforts must also be directed toward defining the sites of action of existing CNS drugs to aid in the design of second-generation agents with improved efficacy and safety.

Address correspondence to: Dr. S. J. Enna, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mail Stop 4016, Kansas City, KS 66160. E-mail: senna{at}kumc.edu