Pharmacology: Receptor Modulation Quiz

Occupancy Theory

• Developed over 100 years ago, observing dye staining specific tissues.
• More dye concentration equates to more staining, leading to the concept of molecules targeting specific sites.

Law of Mass Action

• One drug molecule binds to one receptor molecule and vice versa.
• Response is proportional to occupancy.
• Binding is reversible; negligible drug use implies excess for uniform receptor concentration sensing.

Terms

• [D]: Free drug concentration.
• [R]: Free receptor concentration.
• [DR]: Concentration of drug-receptor complex.
• [DR] + [R] = Total number of receptors.

Drug-Receptor Interactions

• Drug interacts with receptor, reaching equilibrium, forming an activated drug-receptor complex.
• Activated complex leads to response based on intrinsic activity.
• Kon: Rate of drug binding to receptor.
• Koff: Rate of drug dissociation from receptor.

Dissociation Constant (Kd)

• Kd: Measures drug affinity for receptor.
• Kd = Koff / Kon
• Kd = ([D] x [R]) / [DR]

Langmuir Equation

• Relates percent maximal response to drug concentration.
• % Emax = (D / (Kd + D)) x 100
• If Kd = drug concentration, response is 50% of Emax.

Bmax

• Bmax: Total number of receptors; maximal binding.
• Achieved when all receptor sites are occupied.
• Emax is reached when all receptors are bound.

Relationship Between Receptor Occupancy and Tissue Response

• Tissue response is a function of receptor occupancy.
• Langmuir equation describes receptor occupancy.
• Receptor occupancy correlates with drug activation and number of receptors.
• 50% binding yields a 50% response.

Dose-Response Curve

• If Kd = drug concentration, response is 50% of Emax.
• Curve displays 100-fold concentration change (10% to 90% response).
• Changing potency shifts the curve.
• Higher Koff leads to higher Kd and a rightward shift (lower potency).
• Lower Koff leads to lower Kd and a leftward shift (higher potency).

Intrinsic Activity

• All drugs don't activate receptors equally.
• Intrinsic activity assesses how a drug activates a receptor.
• Measured by an alpha factor.

Modified Langmuir Equation

• % Emax = α x (D / (Kd + D)) x 100
• Alpha values: Assess intrinsic activity.

Drug Classes Based on Intrinsic Activity

• Full Agonist (α = 1): Maximal response.
• Partial Agonist (0 < α < 1): Submaximal response.
• Antagonist (α = 0): No response.
• Inverse Agonist (-1 < α < 0): Opposite effect.

Full Agonists

• Bind to receptor, fully activate, achieve maximal response (Emax = Bmax).
• Have an α value of 1.
• Potency determined by EC50, but have equal slopes and Emax.

Partial Agonists

• Bind to receptor, produce partial response.
• Never reach maximal response.
• Potency & Emax differ from full agonists.

Antagonists

• α value of 0.
• Block agonist activation of the receptor.

Competitive Antagonists

• Bind to same site as agonist.
• Rightward shift in dose-response curve; EC50 changes, but Emax stays same.
• Reversible binding.

Non-Competitive Antagonists

• Bind irreversibly, or bind to a different site.
• Reduce Emax, regardless of agonist concentration.
• Irreversible binding; agonist cannot reach Emax.

Spare Receptors

• Receptors not fully occupied to achieve maximal response.
• Magnitude of response isn't proportional to receptor occupancy.
• Emax achievable without occupying all receptors.

Experimental Observation of Spare Receptors

• EC50 and Kd values differ when spare receptors present.
• If all receptors needed, EC50 = Kd.
• If fraction of receptors needed, EC50 < Kd.

Effect of Non-Competitive Antagonists

• Reduce Emax due to inability of agonist to overcome antagonist.
• With spare receptors, low concentrations of non-competitive antagonists don't affect Emax Initially, looking like competitive antagonists.
• High concentration reduces Emax.

Clinical Importance of Spare Receptors

• Protect against disease or irreversible antagonists.

Receptor Binding and Activation

• Receptor interacts with ligand.
• Affinity: Ligand binding strength.
• Agonist: Activates receptor, producing response.
• Antagonist: Prevents response.

Comparing Ligand Activities

• Potency: Drug concentration for maximal effect.
• EC50: Drug concentration for 50% maximal effect.
• Efficacy: Maximal response achievable by a drug.
• Emax: Maximal response.

Agonist Mode of Action

• Full agonist: Stabilizes active state, maximal response.
• Partial agonist: Stabilizes intermediate state, submaximal response.
• Inverse agonist: Stabilizes inactive state, opposite effect.
• Antagonist: Blocks receptor, no response.

Allosteric Modulators

• Bind to different site from orthosteric site.
• Modulate ligand effect.
• Positive PAM increases, Negative NAM decreases response.
• Silent SAMs have no effect on activity.

Receptor Classes

• Ligand-gated channels, metabotropic receptors, nuclear receptors, enzyme-linked receptors.

G-Protein Coupled Receptors (GPCRs)

• Transduce signals.
• Target hormones/neurotransmitters.
• Couple with effector system to mediate signaling.

Case Studies: Modes of Action

• Opioid receptor example (partial agonist Buprenorphine).
• Histamine receptor example (inverse agonist antihistamines).

Comparing Inverse Agonists and Antagonists

• Inverse agonist reduces/blocks receptor activity by binding to inactive state; can block agonist, not inverse agonist.
• Antagonist blocks agonist, and blocks inverse agonist; does not elicit a receptor response.

Ligand-Gated Ion Channels

• Drug binding opens ion channels (selective ions).
• Modulate membrane potential.

GABA-A Receptors and Benzodiazepines

• Benzodiazepines are allosteric modulators.

Module Summary

• Covered agonist types (full, partial, inverse).
• Defined intrinsic activity, allosteric modulators, and receptor classes.
• Presented case studies demonstrating different modes of action.