General Principles Of Pharmacology/Occupation theories
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A.J. Clark (1926, 1933): Clark assumed that the magnitude of the response is directly proportional to the amount of drug
bound. This implies: (1) that the pharmacological effect of a drug is directly proportional to the number of receptors occupied
by the drug and (2) that the maximal response is obtained only when all receptors are occupied. This notion is summarized in the
following equation.
Response = (Response)Max [D] / [D] + KD
The problems with Clark's ideas were that partial agonism, discrepancies between EC50 and KD values, and the existence of spare receptors could not be explained. Thus, this theory is too simple to be applicable except in very limited circumstances.
E.J. Ariëns (1954): Ariëns divided the biological response into two separate parameters, affinity and intrinsic activity.
Affinity described the attachment of the drug to the receptor and was assumed to be governed by mass action. Intrinsic activity
was related to the ability of the drug to induce an effect after binding. This is summarized in the following equation where
alpha is the intrinsic activity.
Response = ∞(Response)Max [D] / [D] + KD
The assumptions are the same as those for Clark's theory; however, the notion of partial agonism could be accounted for by
assuming a lower intrinsic activity for a partial agonist than for a full agonist. Again, however, a discrepancy between EC50 and
KD values and the existence of spare receptors could not be explained.
R.P. Stephenson (1956): Stephenson assumed that the drug-receptor complex provides a stimulus (S) to the tissue, and the
stimulus is directly proportional to the fraction of receptors occupied. The response is then related to the stimulus by an
unspecified function. The proportionality factor between the fractional occupancy of the receptor population and the stimulus was
defined as the efficacy (e). The efficacy of a drug refers to the action of the drug in a particular tissue--it is a measure of
the ability of the drug to produce a response in a given tissue. An additional parameter, intrinsic efficacy (epsilon), was
defined to described the "stimulant activity" of the drug itself, independent of the tissue. The efficacy is related to the
intrinsic efficacy by the following relation:
e= ∈[Rt]
The stimulus is then defined as
S = e [D]/[D]+ KD = ∈[Rt][D] /[D]+ KD
Likewise, the response could be defined as follows:
Response = f(S)= f ( ∈[Rt][D] /[D]+ KD )
This formulation was successful in that it accounted for discrepancies between EC50 and KD and was capable of explaining partial
agonism and spare receptors. The problem with Stephenson's model is that the exact linkage between effect and occupancy remains
unclear.
This formulation was successful in that it accounted for discrepancies between EC50 and KD and was capable of explaining partial agonism and spare receptors. The problem with Stephenson's model is that the exact linkage between effect and occupancy remains unclear.
Rate Theory
Rate theory was developed by W.D.M. Paton (1961) and postulates that the biological response is proportional to the rate at which the drug combines with the receptor--that is, each association of the drug with receptor results in a quantum of excitation. This implies that an agonist must dissociate rapidly from the receptor to enable other successful associations and subsequent generation of quanta of excitation. On the other hand, an antagonist is assumed to dissociate slowly to prevent the generation of other quanta of excitation. Thus, the dissociation rate constant was considered to be the factor which determined whether a drug was an agonist, antagonist or partial agonist. Although compelling, the experimental analysis of drug dissociation rates did not support this model.
Allosteric Theories
Two allosteric models, originally developed to describe enzyme regulation, have been proposed: the Monod, Wyman and Changeux model (MWC model, 1965) and the Koshland, Nemethy, and Filmer model (KNF model, 1966). Briefly, the idea is that receptors can exist in a variety of discrete conformational states differing in the ability of that state to produce a response. Drugs then interact with the receptor in such a way so as to control the conformational state. The MWC model assumes that conformational states exist independently of the drug and that the drug simply controls in which conformational state the receptor exists. A drug acts as an agonist, antagonist, or partial agonist depending upon its affinity for active or inactive states of the receptor. The KNF model states that the drug can induce new conformational states in the receptor. A drug acts as an agonist, antagonist, or partial agonist based on its ability to induce conformational states that are active or inactive. These models define precisely the relationship between binding and effect. The problem is that many conformational states of the receptor may have to be proposed to describe the exact linkage and, in order to define the relationship between binding and response, all of these equilibrium and isomerization constants have to be determined. This can be an overwhelming task even for very simple systems.
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