Drug Receptor Interactions

Drug-receptor interaction is characterized by:

1. binding of drug to receptor and
2. generation of a response in a biological system.

The binding of drugs to receptors can involve all known types of interactions, namely: ionic, hydrogen bonding, hydrophobic, van der Waals, and covalent.
If binding is covalent, the duration of drug action is frequently, but not necessarily, prolonged.
Non-covalent interactions of high affinity also maybe essentially irreversible. The strength of the reversible interaction between a drug and its receptor, as measured by their dissociation constant, is defined as the affinity of one for the other. Both the affinity of a drug and its intrinsic activity are determined by its chemical structure. Binding of a drug molecule may or may not result in activation of the receptor. 
Receptors can be activated or inactivated by either endogenous (such as hormones and neurotransmitters) or exogenous (such as drugs) agonists and antagonists, resulting in stimulating or inhibiting a biological response.
An endogenous agonist for a particular receptor is a compound naturally produced by the body that binds to and activates that receptor. For example, the endogenous agonist for serotonin receptors is serotonin, and the endogenous agonist for dopamine receptors is dopamine.

Types of Agonists

1. Full agonists: They bind and activate a receptor, displaying full efficacy at that receptor. This means that they can elicit maximal tissue response. One example of a drug that acts as a full agonist is isoproterenol, which mimics the action of adrenaline at β adreno-receptors. Another example is morphine, which mimics the actions of endorphins at μ-opioid receptors throughout the central nervous system.
2. Partial agonists: They also bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. These are drugs with intermediate levels of efficacy, such that even when 100% of the receptors are occupied the tissue response is submaximal. Examples of drugs that are partial agonists include buspirone, aripiprazole, buprenorphine, and norclozapine.
3. An inverse agonist: This can have effects similar to those of an antagonist, but causes a distinct set of downstream biological responses. Constitutively active receptors that exhibit intrinsic or basal activity can have inverse agonists, which not only block the effects of binding agonists like a classical antagonist but also inhibit the basal activity of the receptor. Many drugs previously classified as antagonists are now beginning to be reclassified as inverse agonists because of the discovery of constitutive active receptors. Antihistamines, originally classified as antagonists of Histamine 1 receptors have been reclassified as inverse agonists.

Receptor Antagonist

A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses.
In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, and binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active site or to allosteric sites on receptors, or they may interact at unique binding sites not normally involved in the biological regulation of the receptor’s activity. 

Factors that Affect Receptor Response to Drugs

1. Affinity refers to the degree of effectiveness of the interaction between a drug and a receptor. It is a measure of the ability of the drug to bind to its molecular target. The magnitude of response elicited by a drug is directly proportional to the number of receptors occupied by the drug. But the percentage of the total receptors occupied by a drug is a function of the drug concentration as well as of the drug ability to combine with its receptors. The ability of a given drug to combine with its receptors is a constant Ke also known as affinity constant. Different drugs have different affinities for same receptor site. The greater the affinity of a drug, the greater the propensity to bind with a given receptors and the greater the value of Ke. Therefore to produce effect of equal intensity requires lower concentration of a drug with higher affinity than drug with a lesser affinity.
2. Potency : Potency is determined simply by the dose needed to produce a particular effect of a given intensity. Only drugs that act on same group of receptors and are capable of eliciting the same maximal response can be compared with respect to potency. The potency of an agonist is inversely related to its EC50value. The EC50 can be measured for a given agonist by determining the concentration of agonist needed to elicit half of the maximum biological response of the agonist. The EC50 value is useful for comparing the potency of drugs with similar efficacies producing physiologically similar effects. The smaller the EC50 value, the greater the potency of the agonist the lower the concentration of drug that is required to elicit the maximum biological response. Potent drugs are those which elicit a response by binding to a critical a critical number of a particular receptor type at low concentrations(high affinity) compared with other drugs acting on the same system and having lower affinity and thus requiring more drug to bind to bind to same number of receptors.
3. Efficacy: This refers to the magnitude of response produced from the interaction between a drug and its receptor. It is that property intrinsic to a particular drug that determines how “good” an agonist the drug is. Thus, a drug with high efficacy may elicit full response at some concentrations whereas drug with lower efficacy at same receptor may not elicit a full response at any dose. Since the effects of the drugs in the humans are often compared as physiological outcome of treatment (eg diuresis) rather than comparisons of drugs at the same receptor, the term relative efficacy is used to characterize one drug versus the other. Thus, the relative efficacy of loop diuretics in treatment of heart failure is high compared to thiazide diuretics, which is very low.

References

1. Merck Manual
2. Pubmed