Receptor Binding and Affinity

Receptor Basics

• Receptors are protein macromolecules inserted across the cell's lipid bilayer.
• Receptors perform two main functions: recognizing extracellular molecules and transducing signals to change cell activity.
• Receptors bind specific chemicals like hormones or neurotransmitters with high specificity.
• Receptors are named or classified based on the drugs that bind to them.
• Nicotinic acetylcholine receptors bind acetylcholine and the exogenous drug nicotine.
• Pharmacologists design drugs to target specific receptor subtypes in different cells, leading to more selective drugs with fewer side effects.

Drug Binding and Affinity

• Drug (D) binding to a receptor (R) is typically reversible, represented as D + R ⇌ DR.
• A plot of the proportion of receptors occupied (p) against drug concentration [D] forms a rectangular hyperbola.
• A plot of the proportion of receptors occupied (p) against log [D] forms a symmetrical sigmoid curve.
• Affinity is quantified as the molar concentration of a drug required to occupy 50% of receptors at equilibrium, denoted as KD.
• High affinity drugs have a low KD, often in the micro (10^-6) or nano (10^-9) molar range.
• KD represents the equilibrium dissociation constant.
• k+1 and k-1 are rate constants indicating the likelihood of forward and backward reactions.
• At equilibrium, the backward rate equals the forward rate.
• KD is a measure of how tightly a receptor holds onto a drug once they come together.
• Receptors are continually bombarded by chemicals, but only those with high affinity bind strongly.
• High affinity drugs (low KD) bind for a relatively long time due to a slow dissociation rate (k-1 is very small).

Agonists and Efficacy

• Many drugs bind to receptors and occupy them, but do little else.
• Agonists bind and then activate the receptor, exhibiting efficacy.
• Agonists binding induces a conformational change in the receptor, leading to a cellular or tissue response.
• Activation of a receptor (R) by an agonist (A) produces a biological response, represented as A + R ⇌ AR → AR* → response.
• Efficacy describes a drug's ability to activate the receptor i.e. the AR to AR* transition.
• Adrenaline activates its receptor by causing a conformational change, despite being the size of a single amino acid.

Types of Agonists

• Agonists bind to the receptor and activate it, exhibiting efficacy.
• Naturally occurring hormones and neurotransmitters like adrenaline, acetylcholine, and insulin are agonists.
• Agonists can be full or partial.
• Full agonists have high efficacy.
• Full agonists effectively activate receptors and produce a strong biological response.
• Full agonists can produce a maximal response while activating only a fraction of available receptors, indicating spare receptors.
• Partial agonists have low efficacy.
• Partial agonists are less effective at activating receptors and producing a biological response.
• Partial agonists often fail to produce a full response, even when occupying all available receptors.
• Differences between full and partial agonists can be seen in log concentration.

EC50 vs KD

• The EC50 for an agonist is not the same as the concentration required to occupy 50% of the receptors (KD).
• The overall response to an agonist is determined by both its affinity and efficacy; receptor occupancy is determined only by affinity.
• Numerous steps exist between agonist drug binding and the measured response.

Antagonists and Forms of Antagonism

• Antagonists inhibit the effects of a neurotransmitter, hormone, or another drug.
• Many clinically useful drugs are antagonists.
• Chemical antagonism involves one drug chemically inactivating another.
• Dimercaprol in arsenic poisoning is an example of chemical antagonism.
• Pharmacokinetic antagonism involves one drug altering how the body processes another.
• Antacids reducing the absorption of phenytoin is an example of pharmacokinetic antagonism.
• Physiological antagonism involves two drugs producing opposing effects to cancel each other out.
• Noradrenaline increases heart rate while acetylcholine decreases it is an example of physiological antagonism.

Competitive and Non-Competitive Antagonists

• Competitive antagonists compete with the agonist for the same receptor site.
• Competitive antagonists have affinity but do not activate the receptor (zero efficacy).
• Competitive antagonists can be reversible or irreversible.
• Non-competitive antagonists act at a different site on the receptor or another molecule closely associated with it.
• Non-competitive antagonists can be reversible or irreversible.

Reversible Competitive Antagonists

• Pancuronium, cetirizine, and propranolol are examples of reversible competitive antagonists.
• Reversible competitive antagonists inhibit the effects of a neurotransmitter or hormone.
• The inhibitory effects of reversible competitive antagonists can be overcome by increasing the agonist concentration.
• Reversible competitive antagonists produce a parallel shift to the right of the agonist log concentration vs response curve.

Irreversible Competitive Antagonists

• Irreversible competitive antagonists shift the agonist log concentration-response curve.
• The shift caused by irreversible competitive antagonists is not parallel.
• The inhibition produced by irreversible competitive antagonists cannot be overcome by increasing the agonist concentration.
• The inhibitory effects of irreversible competitive antagonists is insurmountable.