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insights LIFESCIENCELEADER.COM JULY 2014 40 DRUG DISCOVERY THE EVOLVING ROLE OF DRUG MECHANISM OF ACTION IN DRUG DISCOVERY AND DEVELOPMENT By S. Lederman W S E T H L E D E R M A N , M . D . The Evolving Role Of Drug Mechanism Of Action In Drug Discovery And Development hile important, these uses and achievements reflect only a narrow view of the utility of drugs. Drugs are not only therapeutic or prophylactic, but also tools that can define the disor- ders they treat and unlock the mysteries of disease processes. The explosive evo- lution of drugs that affect the CNS illus- trates these roles of drugs and also reveals distinct roles of fundamental discoveries and incremental advances. For CNS condi- tions, fundamental discoveries have been primarily driven by clinical observations of unexpected benefits. The incremental advances have been facilitated by under- standing how drugs work, or their mecha- nism of action. For example, understanding the history of drug discovery may facilitate the discovery of drugs that improve sleep quality and treat sleep disorders. Such a drug may also be a tool to unlock the mys- teries of sleep physiology, sleep disorders, and the roles of disturbed sleep in the chro- nicity of pain and the reexperiencing of painful memories. Drug discovery can be viewed as an evo- lutionary process with rare fundamental discoveries interspersed within the more numerous incremental advances. The fundamental discoveries lead to branch points, while the incremental improve- ments march forward in a steady and relatively linear progression. When little was known about biology, drugs were discovered only by a directed but shot- gun approach of human investigation that is sometimes mistaken for seren- dipity. Typically, natural products were tested on a variety of disorders. We can surmise that occasionally the trained eye of a physician or pharmacist noticed a benefit and then pursued a tinkering approach of adjusting the dose and treat- ment regimen to improve on it. Gradually, the active substances were extracted to varying degrees of purification. Together, improved dose regimens and purer ingre- dients led to progress in treating many conditions. Some important CNS drugs (e.g., Aspirin, Oxycodone) were improved through chemical modifications that were revolutionary in their time. The 1950s represented a huge leap in the development of psychotropic drugs. Thorazine, Miltown, Tofranil, and Valium were all developed during this time. The rapid invention and development of these drugs gave birth to what is now called biological psychiatry, because these drugs revealed biological mecha- nisms underlying conditions that had previously been described only clinically. THE POWER OF REPURPOSING This explosion of drugs that revolutionized psychiatry also reveals a theme. Almost all of these drugs had been developed or used for a different purpose than the one for which they ultimately were found effective. Thorazine was developed as an antihis- tamine before it became the first antipsy- chotic. The parent of Miltown was a preser- vative for antibiotics before it became the first anxiolytic. Tofranil was designed to be a follow-on antipsychotic before it became the first tricyclic antidepressant. The revo- lution in biological psychiatry reveals the theme that fundamental discovery can be driven by clinical insights from unexpected drug effects. When clinical observations of unexpected effects lead to new drug approvals, it is called "repurposing." This power of repurposing to drive fundamental discovery is particularly powerful for con- ditions with no known animal model and insufficient knowledge on which to con- struct a biological basis. The CNS drugs that revolutionized psy- chiatry also came to play a role in defining the illnesses they treat. The psychosis of schizophrenia became that condition that responded to chlorpromazine. Anxiety became that condition that responded to Miltown, or later, Valium. Endogenous depression became that condition that responded to Tofranil. Before biological psychiatry was born in the 1950s, psychia- trists focused on the content of a patient's Discovering a new drug can reduce pain and suffering, preserve and extend life, and facilitate procedures like surgery and recovery through anesthesia and pain management. Collectively, effective drugs and their appropriate use can support the creative and cultural activities of societies. 0 7 1 4 _ D r u g _ D i s c o v e r y _ T o n i x - 1 . i n d d 1 0714_Drug_Discovery_Tonix-1.indd 1 6 / 2 0 / 2 0 1 4 1 : 0 0 : 1 8 P M 6/20/2014 1:00:18 PM