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From nicotine to muscle paralysis: How does Langley upend traditional ideas about how drugs work?
In the early 20th century, it was generally believed that the effects of drugs occurred directly at nerve endings. However, John Newport Langley came up with a different idea in 1901, overturning the basic understanding of the effects of drugs. Langley pioneered the receptor theory when he observed that nicotine could still have an effect on the sympathetic ganglia after nerve severing.
The concept of receptor
Langley introduced an innovative concept in 1905: there is a "receptive substance" on the surface of the muscle, which is the medium for drug action. He postulated that these receptors differed in different species, a theory known as the receptor theory. At this time, Paul Ehrlich was trying to understand the rationale for specific selection of various drugs and trying to combine this with the selectivity of the immune response. The formulation of these theories provides the basis for receptor-mediated interactions of drug action.
The nature of receptor-drug interactions
Langley, along with Alfred Joseph Clark and others, developed the receptor occupancy model, which describes the behavior of receptors under the action of drugs.
This model is the first to systematically apply mathematical methods to the interaction between drugs and receptors, revealing the relationship between drug concentration and biological effects. According to this model, the size of the response is directly proportional to the number of receptors occupied by the drug.
Development of competitive inhibition model
Gaddum's classic theory of drug antagonism was developed with the work of Langley and Clark, who described a model in which two ligands compete for binding to the same receptor. The core of this theory is based on the saturability and limited binding sites of the receptor, allowing drug antagonists to effectively affect the effects of agonists.
Dual-state receptor theory and ternary complex model
In order to solve the problem of partial agonists, Langley later introduced the two-state receptor theory, emphasizing the active state transition of the receptor. This model not only illustrates the binding of ligands to receptors, but also reveals the interactions between different receptor states. The ternary complex model further clarifies the relationship between receptors and G proteins, providing a more comprehensive framework for drug action mechanisms.
Assumptions of receptor theory
The receptor must be structurally and stereospecifically specific, and its binding sites are limited.
In addition, the affinity of the receptor for the endogenous ligand must be extremely high and the recognition chemical events should occur immediately upon ligand binding. These hypotheses not only deepen our understanding of drug interactions, but also provide theoretical guidance for the development of new drugs.
Conclusion
Langley's research significantly changed people's understanding of the effects of drugs, thus leading to the development of modern pharmacology. His perspective is not limited to single drug effects but extends to complex biological interactions. Faced with the current integration of data science and drug development, are there more unexplored receptor-drug interaction modes that trigger our deeper thinking?
