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The Evolving Role Of Drug Mechanism Of Action In Drug Discovery And Development

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By Seth Lederman, M.D., cofounder, CEO, and chairman, Tonix Pharmaceuticals

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.

While 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 disorders they treat and unlock the mysteries of disease processes. The explosive evolution of drugs that affect the CNS illustrates these roles of drugs and also reveals distinct roles of fundamental discoveries and incremental advances. For CNS conditions, fundamental discoveries have been primarily driven by clinical observations of unexpected benefits. The incremental advances have been facilitated by understanding how drugs work, or their mechanism 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 mysteries of sleep physiology, sleep disorders, and the roles of disturbed sleep in the chronicity of pain and the re-experiencing of painful memories.

Drug discovery can be viewed as an evolutionary process with rare fundamental discoveries interspersed within the more numerous incremental advances. The fundamental discoveries lead to branch points, while the incremental improvements march forward in a steady and relatively linear progression. When little was known about biology, drugs were discovered only by a directed but shotgun approach of human investigation that is sometimes mistaken for serendipity. 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 treatment regimen to improve on it. Gradually, the active substances were extracted to varying degrees of purification. Together, improved dose regimens and purer ingredients 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 mechanisms underlying conditions that had previously been described only clinically.

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 antihistamine before it became the first antipsychotic. The parent of Miltown was a preservative 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 revolution 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 conditions with no known animal model and insufficient knowledge on which to construct a biological basis.

The CNS drugs that revolutionized psychiatry 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, psychiatrists focused on the content of a patient’s thoughts and words. After the introduction of effective medicines, psychiatrists focused on treating the biological processes underlying patients’ symptoms and diseases in the realms of mood, anxiety, and thought disorders.

Beyond their role in treating disease, drugs have helped scientists understand the biology underlying patients’ symptoms and diseases. A drug’s mechanism of action ultimately involves interactions between the drug and its targets. Drug targets are molecules in humans or pathogens. Sometimes the term “target” is applied to the biological processes that are altered when the drug interacts with its molecular target. Sometimes the term “target” is applied to a disease state.

Understanding a drug’s mechanism of action typically takes many years. Often, innovative drugs have been adopted into clinical use for many years before their mechanism is understood. In fact, the effectiveness of an innovative drug typically has provided scientists with the insight that a target molecule, biological process, or pathological condition exists. Moreover, the drug itself typically has provided scientists the tool to decode its own mechanism. In this way, drug discovery provides not only therapeutics to alleviate human suffering, but also provides profound insights into biology and disease processes.

After the explosion of new psychiatric drugs in the 1950s, research into their structure and mechanism fueled incremental discoveries that led to numerous follow-on drugs, which extended and improved the therapeutic effects of their ancestors. Many antipsychotics followed chlorpromazine and these “typical” antipsychotic drugs were ultimately supplanted largely by “atypical” antipsychotics, particularly Clozaril.

The history of CNS drug discovery and evolution supports the contention that the tremendous therapeutic impact of drug discovery is complemented by the use of drugs as tools to define the disorders they treat and to unlock mysteries of disease processes. Fundamental discoveries and incremental evolution play distinct roles in the evolution of increasingly effective and more tolerable drugs. Fundamental discoveries help decode mechanisms which facilitate the incremental advances of medicinal chemistry. Without animal models for many of the important human psychiatric and pain conditions, fundamental discoveries have been driven by clinical observations of unexpected benefits.

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