Receptor Occupation Theory

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Chapter: Essential pharmacology : Pharmacodynamics Mechanism Of Drug Action; Receptor Pharmacology

After studying quantitative aspects of drug action, Clark (1937) propounded a 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,


RECEPTOR OCCUPATION THEORY

 

After studying quantitative aspects of drug action, Clark (1937) propounded a 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, viz. 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:

 


 

Subsequently, it has been realized that occupation of the receptor is essential but not itself sufficient to elicit a response; the agonist must also be able to activate (induce a conformational change in) 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 (IA) 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 in the Clark’s equation:

 


 

Depending on the agonist, DR could generate a stronger or weaker S, probably as a function of the conformational change brought about by the agonist in the receptor. Accordingly:

 

Agonists have both affinity and maximal intrinsic activity (IA = 1), e.g. adrenaline, histamine, morphine.

 

Competitive Antagonists have affinity but no intrinsic activity (IA = 0), e.g. propranolol, atropine, chlorpheniramine, naloxone.

 

Partial Agonists have affinity and submaximal intrinsic activity (IA between 0 and 1), e.g. di chloro iso-proterenol (on β adrenergic receptor), pentazocine (on μ opioid receptor).

 

Inverse Agonists have affinity but intrinsic activity with a minus sign (IA between 0 and –1), e.g. DMCM (on benzodiazepine receptor).

 

It has also been demonstrated that many full agonists can produce maximal response even while occupying <1% of the available receptors.

A large receptor reserve exists in their case, or a number of spare receptors are present.

 

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