Theories of Receptors

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Chapter: Medicinal Chemistry : Receptors

Proposed by Gaddum and Clark, the theory states that the intensity of pharmacological effect is directly proportional to the number of receptors occupied by the drug.


THEORIES OF RECEPTORS


Occupation Theory

Proposed by Gaddum and Clark, the theory states that the intensity of pharmacological effect is directly proportional to the number of receptors occupied by the drug. The pharmacological response of a drug molecule depends on the amount of dose, the total number of receptors available, and its intrinsic activity that can be expressed as K1[R] × [A].

where 

K1 = association constant

R = concentration of the receptors not occupied by drugs

A = concentration of drug molecules or dose

Similarly, the rate of dissociation of the drug receptor complex is given by the expression K2 [RA].

K2 = dissociation constant

[RA] = concentration of receptors occupied by the drug 

At equilibrium, K1[R] × [A] = K2[RA]

[R] + [RA] is equal to [r] = total concentration of the receptors.

Thus, K1[A] [r] – [RA] = K2 [RA]                 ……..(1)

or

[RA]/[r] = K1[A]/K1[A] + K2 = 1/1 + K2/K1[A]          ………………..(2)

K2/K1 can be replaced by KA = equilibrium constant. 

It is the reciprocal of the drugs affinity for the receptors.

The term [RA]/[r] represent the fraction of the total number of receptors occupied by the drug.

When [RA] = [r], that is, all receptors are occupied and the response is, thus, proportional to its intrinsic activity Xn

Relative response = [RA]X/[r] = X/1 + KA/[A]          …………………….(3)

This theory does not rationalize partial antagonists.


Rate Theory

The rate theory explains that the pharmacological activity is a function of the rate of association and dissociation of a drug with the receptor and is not the function of the number of occupied receptors.

At equilibrium, the rates of combination and dissociation of drug-receptor reactions are same and Eqn (1) can be written as

K1[A] ([r]-[RA])/[r] = K2 [RA]/[r]         ……………….(4)

or

Rate of receptor occupation = K2/1 + RA/[A] ---(5)

When the response is proportional to the number of receptors occupied, Eqn (3) is important and when the response is proportional to the rate of receptors, Eqn (5) is important.


Induced Fit Theory

It is proposed by Koshland to give explanation for the action of enzymes and substrates. It explains that the receptor (enzyme) need not necessarily exist in the same conformation that is required to bind the drug (substrate). As the drug approaches the receptor, a conformational change is induced for binding, which initiates the pharmacological activity.

Example: Acetylcholine interacts with the regulating protein and alters the normal forces that stabilizes the structure of the protein and thereby producing a transient rearrangement in membrane structure and a consequent change in its ion regulating property. These receptors are suggested to be elastic and returns to the original conformation after the drug releases.

According to this theory, an agonist will bind by conformational change with intrinsic activity and elicit a response, but an antagonist will bind by conformational change without intrinsic activity.


Macromolecular Perturbation Theory

According to this theory, the drug interaction with a receptor leads either to specific conformational perturbations (SCPs) or to nonspecific conformational perturbations (NSCPs). An SCP will produce a specific response from an agonist in which the drug possesses intrinsic activity. In NSCP, no stimulant action, but may be antagonistic or blocking action will be produced. If a drug possesses SCP and NSCP features, an equilibrium mixture of two complexes may result and leads to partial agonistic action.

Example: Alkyl trimethyl ammonium ions

C1 to C6—Alters receptor structure and produces muscarnic agonistic action 

C8 to C12—Antagonistic action

Heptyl and octyl derivatives—Partial agonists (intermediate derivatives)


Activation–Aggregation Theory

According to this theory, even in the absence of drugs, a receptor is in a state of dynamic equilibrium between an activated form (Ro), which is responsible for biological responses and an inactive form (To). Agonists shift the equilibrium to activated form and antagonists shift the equilibrium to inactivated form. Partial agonists bind to both conformations during partial antagonistic action. The agonist-binding site and antagonist-binding site conformation may be different.


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