2

Basic Principles of Drug Design II

Receptors: structure and properties

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2.1 THE RECEPTOR CONCEPT AND ITS HISTORY

Along with improved methods for understanding and designing drug molecules, the other
central theme of medicinal chemistry over the past 40 years has been the elucidation of
the structure and function of drug receptors, an endeavour that continues unabated in the
21st century. This is not surprising, given the importance of the receptor to the pharma-
codynamicphase of drug action. Specific drugs (i.e., those that act at very low concen-
trations) exert their effects by interacting with a specific macromolecular structure (the
receptor) in the living cell. This results in the brief formation of a reversible drug–receptor
complex. This, in turn, triggers a secondary mechanism such as the opening of an ion
channel, or catalyzes the formation of a second messenger, often cyclic AMP (cAMP).
Other molecular participants within this chain reaction, such as kinases, are then activated.
This cascade of events finally results in the physiological (and hopefully therapeutic)
change attributed to the drug. The same mechanisms also operate with endogenous agents
such as hormones and neurotransmitters.
It is generally accepted that endogenous or exogenous agents interact specifically
with a receptor site on a specialized receptor molecule. Drug interaction with this site
of binding, which has chemical recognition properties, may or may not trigger the
sequence of biochemical events discussed above; therefore, one must distinguish care-
fully between sites of action (true receptors) and sites of binding (silent receptors or,
occasionally, separate allosteric antagonist-binding sites).
The receptor concept dates back to 1878. The notion was initially formulated by John
Langley, a British physiologist who worked on the biological properties of atropine (2.1)
and pilocarpine (2.2) (see section 4.2). However, the actual term receptorwas first intro-
duced in 1907 by Paul Ehrlich, the famous pioneer of chemotherapy and immunochem-
istry. His concepts of receptor binding (corpora non agunt nisi fixata—“compounds do
not act unless bound”), bioactivation, the therapeutic index, and drug resistance are still
valid in principle, though they have undergone considerable expansion and refinement.
The early history of the receptor concept is recounted by Parascandola (1980).