being composed of more than one protein; facilitatory and inhibitory interactions exist
between these subunits and may alter the drug–receptor interaction. Finally, some receptors
are not only dynamic in terms of their shape, but also mobile, drifting in the membrane
like an iceberg in the ocean.
2.7.2.1 The Two-State Receptor Model
The two-state receptor model (also known as the Monod–Wyman–Changeux model)
was developed on the basis of the kinetics of competitive and allosteric inhibition as
well as through interpretation of the results of direct binding experiments. This model
postulates that, regardless of the presence or absence of a ligand, the receptor exists in
two distinct states, the R (relaxed, active, or “on”) and T (tense, inactive, or “off”)
states, which are in equilibrium with each other. An agonist (drug, D) has a high affin-
ity for the R state and will shift the equilibrium to the right; an antagonist (inhibitor, I)
will prefer the T state and will stabilize the TI complex. Partial agonists have about
equal affinity for both forms of the receptor.
Some members of a receptor population are in the R state, even in the absence of any
agonist. Thus, the receptor can be thought of having a “tone” like a resting muscle. The
ratio of states is defined by the equilibrium constants KL,KT, andKR(for drug D or
inhibitor I), and gives true physicochemical meaning to the concept of intrinsic activity.
In contrast to the assumption made in the classical occupation theory, the agonist in
the two-state model does not activate the receptor but shifts the equilibrium toward the
R form. This explains why the number of occupied receptors does not equal the number
of activated receptors.
2.7.2.2 The Receptor Cooperativity Model
Receptor cooperativity, which has largely been studied on hormone receptors, is
explained by further extension of the two-state model. It is assumed that the coopera-
tion of several receptor protomers is necessary for an effect like the opening of an ion
channel, with all of these protomers having to attain an R or a T state to open or close
a pore. This means that the binding sites or the receptor protomers on which these sites
are situated must interact, and, as they do so, their affinity changes as a function of the
proportion of R-state receptors in the assembly. This also means that a drug–receptor
complex can trigger the transition of an unoccupied neighboring receptor from the T to
the R state. If a ligand facilitates binding or the effect of the receptor, the cooperativity
is positive; if it hinders these, the cooperativity is negative (e.g., in the insulin receptor).
Negative cooperativity could also account for the spare receptors (receptor reserve)
seen in many systems. As receptors cluster during their own metabolic cycle, low
ligand occupancy in such clusters may still lead to a large change in the cluster config-
uration, resulting in a full effect without a 1:1 ratio of ligand–receptor binding.
Scatchard plots of ligand binding will be concave for positive and convex for negative
cooperativity. Hill plots can also indicate the type of cooperativity involved.
As is already evident from foregoing discussions, effector or amplifier systems are
the parts of the receptor oligomer which convey the fact that a drug has become bound to
the receptor (or, to be more precise, that there has been a conformational change to the
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