Receptor Occupation Theory

RECEPTOR:  it is defined as a macromolecule or binding site located on the surface of inside the effector cell that serves to recognize the signal molecule/drug and initiate the response to it, but itself has no other function. I have started with receptor, because, the following theory is widely accepted, that is, Receptor Occupation Theory. It’s not only widely accepted, but, by which most of the phenomenon can be explained thoroughly, Clark in 1937 propounded this theory of drug action based on occupation of receptors by specific drugs and that the pace of a cellular function can be altered by interaction of these receptors with drugs which, in fact, are small molecular ligands. He perceived the interaction between the two molecular species, that is, drug (D) and receptor (R) to be governed by the law of mass action, and the effect (E) to be a direct function of the drug receptor complex (DR) formed:

                                             D+R = DR = E 

 Subsequently, it has been realised that occupation of the receptor is essential but not itself sufficient to elicit a response; the agonist must also be able to activate the receptor. The ability to bind with the receptor designated as affinity, and the capacity to induce a functional change in the receptor designated as intrinsic activity or efficacy are independent properties. Competitive antagonists occupy the receptor but do not activate it. Moreover, certain drugs are partial agonists which occupy and sub maximally activate the receptor. An all or none action is not a must at the receptor. A theoretical quantity (S) denoting strength of stimulus imparted to the cell was interposed.
Depending on the agonist, DR could generate a stronger or weakerS, probably as a function of the conformational change brought about by the agonist in the receptor.

 An attractive alternate model for explaining the action of drug known as two-state receptor model

two-state receptor model

has been proposed. The receptor is believed to exist in two interchangeable states: Ra (active) and Ri (inactive) which are in equilibrium. Mostly, for receptors, the Ri state is favoured at equilibrium-no/very weak signal is generated in the absence of the agonist-the receptor exhibits no consecutive activation. The agonist (A) binds preferentially to the Ra conformation and shifts –Ra predominates and a response is generated depending on the concentration of A. the competitive antagonist (B) binds to Ra and Ri with equal affinity –the equilibrium is not altered –no response is generated, and when the agonist is applied few Ra are available to bind it –response to agonist is decreased. If an agonist has only slightly greater affinity for Ra than for Ri, the equilibrium is only modestly shifted towards Ra even at saturating concentrations –a sub maximal response is produced and the drug is called a partial agonist (C). The inverse agonist (D) has high affinity for the Ri state, therefore it can produce an opposite response, provided the resting equilibrium was in favour if the Ra state. Certain ion channel receptors such as benzodiazepine receptor and some G-protein coupled receptors like histamine H2, angiotensin AT1, adrenergic beta 1 and cannabinoid receptors exhibit constitutive activation, that is, an appreciable intensity signal is generated even in the basal state. This model provides an explanation for the phenomenon of positive cooperativity often seen with neurotransmitters and is supported by studies of conformational mutants of the receptor with altered equilibrium. However, receptors are now capable of adopting multiple active and inactive conformations favoured by different ligands.