BS2013 Study Notes: Physiology and Pharmacology - Receptor Responses vs Occupancy

Lecture Overview

  • Course: BS2013 - Physiology and Pharmacology

  • Topic: Receptor responses vs occupancy - Efficacy and the concept of receptor reserve

Receptor Theory

  • Definition of Agonist: An agonist is defined as a drug that binds to a receptor producing a response.

  • Components of Agonist Action: 1. Binding of the drug to the receptor 2. Activation of the receptor, leading to a response.

    • Notation:

    • A + R ⇌ AR ⇌ AR* (Response)

    • Example response: Increase in intracellular calcium ions, e.g. [Ca2+]₁ leading to contraction.

Occupancy and Responsiveness

  • Two Forms of Agonists in Context to Occupancy:

    • Agonist 1 (A): Low occupancy results in minimal binding yet can produce substantial effects.

    • Agonist 2 (A): High occupancy correlates with increased response through enhanced binding and activation.

    • The sequence of reactions occurs as:

    • A + R ⇌ AR ⇌ AR* leads to a Response over time.

Comparing Binding and Agonist Responses

  • EC50: Effective concentration giving 50% of the maximal response.

    • Concept of “receptor reserve”: implies that not all receptors need to be occupied for a maximal response to occur.

    • Notably, some tissues can achieve maximum response with less than 5% occupancy of receptors.

Differences in Response Curves

  • Shape of Response Curves:

    • Both binding and response curves are often sigmoidal in shape and concentration-dependent.

    • Variation exists due to downstream effects; e.g., ACh (acetylcholine) binding to muscarinic receptors leads to a series of reactions:

    • Activation of G-proteins

    • Engagement of second messenger systems

    • Rise in intracellular calcium levels, eventually resulting in contraction.

EC50 as a Measure of Potency

  • Potency: The measurement of an agonist's effectiveness based on its ability to bind and activate a receptor.

    • Note the relationship between concentration and response can be represented in a graphical format displaying increasing potency:

    • Potency is better understood utilizing the relationship of response versus concentration (units in μM).

Signaling Amplification and Receptor Reserve

  • Consequences of Signaling Amplification:

    1. Physiological Efficiency: Small increases in agonist concentration can elicit maximal cellular responses.

    2. Impact of Receptor Loss: Loss of receptors due to age or disease does not directly correlate with decreased function of the cell or organ, as receptor reserves can buffer this loss.

Maximum Response and Efficacy

  • Emax Comparison: Varied responses from different agonists:

    • B and C: Partial agonists

    • A: Full agonist

    • Emax: Significantly measures efficacy, indicated as a percentage of the maximal response.

Affinity and Efficacy

  • Definitions:

    • Affinity: The likelihood of a drug molecule binding to a free receptor at any given moment.

    • Example:

      • Agonist A (full agonist) vs Agonist B (partial agonist) both possess the same KD values.

      • Though they occupy the receptor, Agonist B achieves a sub-maximal response at full receptor occupancy indicating low efficacy.

Fitting Concentration Response Curves

  • Equations:

    • General relationship expressed as:
      Response = \frac{max \cdot [XA]}{[XA] + EC50}

    • where max = maximum response,

    • [XA] = concentration of agonist, and

    • EC50 = concentration evoking 50% of the response.

    • n (slope factor): Reflects steepness of the response curve, commonly termed the Hill slope.

Variation in the Hill Slope

  • Implications of Hill slope differences:

    • % Max response may exhibit clear differences despite having the same maximum response and EC50 concentration.

    • Indications may suggest physiological relationships such as cooperative binding as evidenced by varying Hill slopes (e.g., slope = 1 implies positive cooperativity).

Summary Points

  • Key concepts regarding agonist-receptor interactions:

    • An agonist generates cellular signals and functional responses through binding and activation of specific receptors.

    • Affinity: Defined by the KD value when half the receptors are occupied; relates to the kinetic aspects of drug binding.

    • Efficacy: The capacity of an agonist to produce a functional response, quantitatively measured by EC50, which defines potency irrespective of maximal response.

    • Spare Receptors: Also known as receptor reserves; allow for physiological efficiency by enabling responses with less than full receptor occupancy.

    • Distinction made between partial agonists (less effective) and full agonists (more effective) based on the capability to elicit maximum responses.

Additional Details on Efficacy

  • Intrinsic Efficacy: The intrinsic capacity of an agonist to activate a receptor, consequently leading to a cellular response.

  • Overall efficacy generates from the binding and intrinsic properties of the agonist:

    • Simple binding relationship represented as:
      A + R ⇌ AR ⇌ AR* (Response)

Historical Context

  • Archibald Vivian Hill (1888-1977):

    • Notable for his 1910 research on oxygen binding to hemoglobin, focusing on how binding affinity varied with oxygen partial pressure.

    • Introduced the concept of the Hill slope (n), critical for understanding the cooperative binding among molecules targeting hemoglobin and applicable in pharmacology.