VPT 311: General and Systemic Veterinary Pharmacology (2+1)

RECEPTOR THEORIES

Occupation theories

• A.J.Clark propounded the occupation theory which assumes that the extent to which a tissue is dependent on the proportion of its receptor population that has been occupied by a drug and maximal response is reached when all the receptors are occupied. He presumed that each occupied receptor delivered a constant unit of response and that this individual occupancy stimuli was summated in mathematical fashion to give a linearly proportional response. But this theory was not applicable in all situations. In the case of partial agonists a maximal response could not be exhibited even though all the receptors were occupied.
• E.J.Ariens, divided the biological response into two separate parameters namely affinity and intrinsic activity. Affinity described the binding 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. The assumptions are the same as those for Clarke’s theory. However, the notion of partial agonism can be accounted for by assuming a lower intrinsic activity for a partial agonist than for a full agonist. Again, a discrepancy between EC50 and KD values and the observations of spare receptors could not be explained.
• R.P.Stephenson, assumed that the drug receptor complex provides a stimulus to the tissues and that 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 was defined as the efficacy. The efficacy of a drug refers to the action of the drug to produce a response in a given tissue. An additional parameter, intrinsic activity was defined to describe the stimulant activity of the drug itself independent of the tissue. The problem with Stephenson’s model is that the exact link between effect and occupancy remains unclear.

Rate theory

• Rate theory was developed by W.D.M. Paton 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 quantum of excitation.
• On the other hand, an antagonist is assumed to dissociate slowly to prevent the generation of other quanta of excitation. Thus, dissociation rate constant was considered to be the factor, which determined whether a ligand was an agonist, antagonist or partial agonist. 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 idea of the allosteric theory is that receptors can exist in a variety of discrete conformational states differing in their ability of that state to produce a response.
• Ligands then interact with the receptor in such a way so as to control the conformational state. These models define precisely the relationship between binding and effect.
• Receptors sub serve two essential function viz., recognition of the specific ligand molecule and transduction of signal with a response. Accordingly, the receptor has a ligand binding domain (spatially and energetically suitable for binding the specific ligand) and effector domain, which undergoes a functional conformational change.