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

Abstract

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.

Extrasynaptic site of action for γ-hydroxybutyrate

“…A dvances in pharmacology often result from identifying the mechanism of action of drugs found empirically to be biologically active (1). γ-Hydroxybutyric acid (GHB), also known as Fantasy, is a centrally active agent that has been used clinically and recreationally for nearly half a century.…”

First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models

“…Since animal models of CNS disorders cannot wholly reflect the human condition, efficacy in more than one clinically-relevant model, including preferably a non-transgenic and a transgenic model, together with evidence of disease-relevant mechanism of action, increases confidence in the translation potential of a drug candidate (Enna and Williams, 2009;Markou et al, 2009). …”

The GABAB receptor as a target for antidepressant drug action

“…Even with this progress, however, little has changed with regard to the types of agents employed to treat this condition, with this class still dominated by drugs that directly interact with monoamine systems (Kelsey and Nemeroff, 1998). This is not due to a lack of effort, as there remains a need for novel treatments (Enna and Williams, 2009). While newer antidepressants are generally safer than older agents, little progress has been made in decreasing the percentage of non-responders and in speeding the onset of action.…”

“…Moreover, as the response to many clinically effective psychotherapeutics involves interactions with multiple sites, it is possible that the most effective antidepressant may be one that targets several transmitter systems. As designing this type of drug is difficult given the number of possible target combinations, such an agent is more likely to be discovered with a pharmacometric approach (Enna and Williams, 2009).…”