2.5 CLASSICAL THEORIES OF DRUG–RECEPTOR
BINDING INTERACTIONS
The classical theories of drug action were developed by Gaddum and Clark in the 1920s
and extended to antagonists by Schild. These ideas were expanded by Stephenson (1956)
and by Ariëns and his school from 1960 to 1980. It is not possible to appreciate and criti-
cally appraise current and rapidly changing ideas on the molecular nature of drug–receptor
interactions without reviewing the classical pharmacological theories. Since about 1970,
progress in methodology has made direct measurement of drug binding to receptors a rou-
tine procedure. The classical theories were of necessity based on measurement of the final
effect of drug action—an effect that is many steps removed from the drug–receptor bind-
ing process. Therefore, the modern approach more closely follows molecular lines whereas
the older classical pharmacological methodology operates at the cellular and organismic
level. Naturally, both avenues have advantages and disadvantages. We shall deal first with
the dose–response relationship before reviewing current receptor models.
The classical occupation theoryof Clark rests on the assumption that drugs interact
with independent binding sites and activate them, resulting in a biological response that
is proportional to the amount of drug–receptor complex formed. The response ceases
when this complex dissociates. Assuming a bimolecular reaction, one can write
where D =drug and R =receptor. The dissociation constant at equilibrium is
The effect (E) is directly proportional to the concentration of the drug–receptor complex:
The maximum effect (Emax) is attained when all of the receptors are occupied:
where the total receptor concentration [RT] is
andαis a proportionality factor. Therefore, from (2.5) and (2.7):
Dividing (2.6) by (2.7):
78 MEDICINAL CHEMISTRY
D+RDR (2.4)
KD=
[D][R]
[DR]
(2.5)
E=α[DR] (2.6)Emax=α[RT] (2.7)[RT]=[R]+[DR] (2.8)
[DR]
[RT]
=
[D]
KD+[D]
(2.9)
[DR]
[RT]
=
E
Emax