Receptor Antagonism

There are two major mechanisms of receptor antagonism: orthosteric, whereby the antagonist and agonist compete for the same binding site on the receptor, and allosteric, whereby each has their own binding site on the receptor and the interaction between them takes place through a conformational change in the receptor protein. It is important to differentiate these since these respective antagonist types have different behaviors in pharmacological and physiological systems.

All equations for orthosteric molecular interaction can be derived from the integral of the differential equation describing the receptor occupancy by an antagonist with time (3pB/dt) as a function of time and the competition between agonist [A] and antagonist [B] for receptors [13]:

where pb is the equilibrium receptor occupancy by antagonist and KA and KB are the equilibrium dissociation constants of the agonist and antagonist receptor complexes, respectively. Upon integration this yields:

Pab = ([A]/Ka / ([A] Ka +1)) • (1 - ( (1 - e-k24t ) + Pb e-k 2" ) ) (1.11) where:

For accurate estimation of KB (1/affinity of the antagonist), there must be enough time elapsed in the experiment for the agonist to re-equilibrate with the antagonist-bound receptors. If there is sufficient time for this to occur (the dissociation rate of the antagonist is rapid such that the agonist can attain correct receptor occupancy) and time/k2 > 10, then Equation 1.11 for receptor occupancy by agonist (PA) reduces to the familiar, and much simpler, equation for simple competitive antagonism presented by Gaddum [14]:

This equation predicts the well-known shift to the right of agonist dose-response curves with no diminution of maxima produced by competitive antagonists (note that agonist (pA) will be complete (pA ^ 1) when [A] >> [B]). On the other hand, if the antagonist has a slow offset, there may not be sufficient time for re-equilibration during the experiments and noncompetitive antagonism may result. Under these circumstances, time/k2 <0.01 and Equation 1.11 reduces to the Gaddum equation for noncompetitive antagonism:

Under these conditions, Equation 1.16 predicts that the presence of the antagonist ([B] ^ 0) essentially precludes complete receptor occupancy by the agonist (PA always <1 with nonzero values of [B]). This can produce dose-response curves with depressed maxima. It can be seen that competitive (surmountable) and noncompetitive (insurmountable) are only kinetic extremes of the same mechanism of drug action (orthosteric binding of antagonist to the agonist binding site).

The other major mechanism for drug-induced receptor blockade is through allosteric interaction whereby the agonist and antagonist bind to their own sites on the receptor, and the interaction between them occurs through a conformational change in the receptor:


The effect of the modulator on the affinity of the receptor for ligand A is quantified by a factor a (designated the cooperativity constant—the use of this symbol should be differentiated from its use denoting intrinsic activity by Ariens); the affinities of ligands A and B for the receptor are Ka and Kb , respectively. Under these circumstances, the effect of an allosteric modulator on the binding of ligand A is given by [15]:

[A]Ka (1 + a[B]/KB ) [A]Ka (1 + a [B]Kb ) + [B]Kb +1

Equation 1.18 defines the changes in affinity of the receptor for A when the modulator B is bound; these can be positive (i.e., increase affinity when a > 1) to yield potentiation of binding or negative (decrease affinity when a < 1) to yield antagonism. Unlike orthosteric antagonism, binding is not precluded by a negative allosteric modulator but rather, the affinity of the receptor is reset to a different level. Also, since allosteric effect is mediated by binding of the modulator at a separate site, it is saturable; that is, when the allosteric sites are completely bound by modulator, the effect reaches a maximal limit.

The other major delineation between orthosteric and allosteric effect is that allosteric effects can modulate agonist affinity and efficacy separately. This is because modulators essentially stabilize a new conformation of the receptor. To describe the effect on agonist efficacy, an extended model of allosteric modulation of receptors is required. Thus, the Ehlert allosteric model [ 15] (scheme 18) is linked to the Black and Leff operational model [12] to yield the following [16-18]:

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