3.

1 RECEPTOR THEORY: HISTORIC PERSPECTIVE

Throughout medical history, doctors and scientists have been intrigued by
the magic of medicines whereby minute amounts of some substances produce
radical change in human behavior and health. The receptor concept was implied
throughout that history. As early as 1685, Robert boyle suggested that different
parts of body have different textures; and therefore, different bounds substances; a
rudimentary idea suggesting the existence of drug receptors.
The concept of receptor is credited to two eminent physiologists, John
Newport Langley and Paul Ehrlich. Central to their independent studies was the
concept of the dependence of physiologic action on chemical structure while a
student at Cambridge in 1874, Langley explained the antagonism of pilocarpine by
atropine. In a paper published in 1878, he foreshadowed the receptor concept.
There is a substance of substances in the nerve endings or gland cells with which
both atropine and pilocarpine are are capable of forming compounds.
In the same year, Paul Ehrlich graduated from the University of Leipzig and, in
this thesis on histologic staining, suggested that staining was the result of chemical
interaction between two compounds. His later work on immunization discussed
receptive side chains. Ehxtich, having read the work of Emil Fischer who
formulated a theory of enzyme action, suggested that these side chains interacted
with toxins as a look and key. These ideas guided his later great work in the field of
chemotherapy.
It was a student at Cambridge University, A.J Clark, who first applied
mathematic principles to drug receptor theory. He studied the effects of
acetylcholine on various isolated tissues and nired that the relationship between
drug concentration and response corresponded closely to the equation:
K . x = y/ (100-y)

(3.1)

Where the x is the drug concentration and y is the percentage of the maximal
response to drug. A rearrangement of equation (3.1) show the form of the familiar
Langmuir adsorption isotherm:

y=

100 x
x+ 1/k

(3.2)

Clark published a treatise in 1937 that cummarized and extended the existing
theories of drug receptors interaction. The major problem at this time was the lack
of knowledge about the relationship between receptor occupancy and tissue
response. Therefore, the simplest assumptions were made in Clarks treatise:

The maximal response to a drug (Em) was the tissue maximal response.

Fractional tissue response (EA/Em) was directly equal to fractional receptor

occupancy ([A.R]/[R1]).

Under these circumstance, the following equation represents the response of

a drug A in a tissue, as described by Clark:

R
[A]
[ 1]=
(3.3)
[ A ]+ K A
EA [ A.R]
=
Em
Where KA is the equilibrium dissociated constant of the drug receptor
complex. Clark recognized that the relationship between receptor occupation by a
drug and the resulting response was not a linear one in most cases and that
therefore drug effect, as described be equation 3.3, was limited.
The impact of Langleys and Ehrlichs and even later, of Clarks, ideas was
limited in their litetimes because they involved molecular concepts in a technology
that could not experimentally test them. This was to change with the concept of
bioassay. Although a diverse number of scientific disciplines contributed to the
concept of specific receptors for chemicals in biological systems, it was through the
method of bioassay that the critical data for the formulation of receptor theory
where obtained. Bioassay, the quantitative measurement of drug effect in intact
biologic system, was pioneered by the great pharmacologists Sir John Gaddum, Sir
Henry Dale, and Harold Burn (2).
The first prerequisite of bioassay was that the measuring system be stable.
The state of the art in pharmacology into the first half of the twentieth century
consisted of a great deal of anecdotal knowledge and creative expertise in
sustaining whole biologic preparation over periods of time during which changes in
tissue state were measured with drug challenge. The major tool for quantitative
pharmacology was the isolated tissue. Thus, whole organs were placed in heated
chambers and incubated with physiologic salt solutions, kept at physiologic pH, and
perfused with oxygen such that they behaved as in the intact organism. The
difference was that the volume perfusing the preparation (and therefore the
receptors) was known, and thus the concentration of drugs at the receptors also
was known (with the obvious caveats to this assumption discussed in chapter 5).
A typical isolated tissue system is shown in figure 3-1. The tissue is placed in
a heated organ bath, and organ function (i.e., contraction) is recorded or a simple
apparatus called a kymograph which consists of a leaver, one end or which is tied to
the tissue and the other to a pen that presses on a smoked rotating drum by gravity.

As the tissue contracts, either spontaneously or it response to a drug, the lever is

pulled upward and a record of the displaced.