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Pharmacodynamics. HuBio 543 September 6, 2007 Frank F. Vincenzi. Receptors, signal transduction, transmembrane signaling Agonist, antagonist, partial agonist, inverse agonist, multiple receptor states Intrinsic activity, efficacy, SAR Desensitization, up and down regulation.

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Pharmacodynamics

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Pharmacodynamics

HuBio 543

September 6, 2007

Frank F. Vincenzi


Receptors, signal transduction, transmembrane signaling

Agonist, antagonist, partial agonist, inverse agonist, multiple receptor states

Intrinsic activity, efficacy, SAR

Desensitization, up and down regulation

Quantification of drug receptor interactions and responses

Potency

Schild equation and regression

Competitive and non-competitive antagonism

Spare receptors

Kd, EC50, pD2, pA2

Learning Objectives


Typical concentration-effect curve(plotted arithmetically)


A slide rule (logarithmic scale)


Typical log concentration-effect curve(graded ‘dose-response’ curve)


Drug(D) - Receptor (R) Interaction

k1

D + R

DR

k2

Kd = ([D] * [R]) / [DR] = k2/k1

Kd = dissociation constant

k1 = association rate constant

k2 = dissociation rate constant


Several ways to express agonist potency &/or apparent affinity of agonists

EC50 (effective concentration, 50%, M)

Kd (apparent dissociation constant, M)

pD2 (negative log of molar concentration (M)

of the drug giving a response, which

when compared to the maximum,

gives a ratio of 2) (i.e., negative log

of half maximal concentration)


The classical concentration-effect relationship and the laws of mass action

Effect = (Effectmax * conc)/(conc + EC50)

In the previous data slide EC50 ~ 3 x 10-9 M

Thus, the apparent Kd of ACh ~ 3 x 10-9 M

IF (NOTE, BIG IF)

EC50 = Kd then

Bound drug = (Bmax * conc)/(conc + Kd)


Binding of a radioligand to tissue samples

Adapted fromSchaffhauser et al., 1998


Scatchard analysis of binding of 125iodocyanopindolol to beta-receptors in human heart

Adapted fromHeitz et al., 1983


Acetylcholine (ACh): One drug with different affinities for two different receptors

(adapted from Clark, 1933)


ACh: Different affinities for different receptors

  • Muscarinic receptors

    • EC50 = apparent Kd ~ 3 x 10-8 M, pD2 ~7.5

  • Nicotinic receptor

    • EC50 = apparent Kd ~ 3 x 10-6 M, pD2 ~5.5

    • In these experiments, affinity of ACh for muscarinic receptors is apparently ~100 times greater than for nicotinic receptors. ACh is 100 times more potent as a muscarinic agonist than as a nicotinic agonist. So, when injected as a drug, muscarinic effects normally predominate, unless the muscarinic receptors are blocked. (No problem for nerves releasing ACh locally onto nicotinic receptors, however).


  • Properties of an agonist (e.g., ACh) (on receptors lacking spontaneous activity)

    • Accessibility

    • Affinity

    • Intrinsic activity > 0


    Different affinities of related agonist drugs for the same receptor: Different potencies

    (adapted from Ariëns et al., 1964)


    Properties of an antagonist (on receptors lacking spontaneous activity)

    • Accessibility

    • Affinity

    • Intrinsic activity = 0


    Pharmacological antagonism in an intact animal


    Properties of a partial agonist (on receptors lacking spontaneous activity)

    • Accessibility

    • Affinity

    • 0 < Intrinsic activity < 1


    Theoretical concentration-effect curves for a full and partial agonist of a given receptor


    Multiple receptor conformational states:How to understand agonists, partial agonists and antagonists


    Simple case: receptor has little or no spontaneous activity in the absence of added drug

    ‘inactive’ R

    ‘active’ R


    An agonist binds more tightly to the ‘active’ state of the receptor: Equilibrium shifts to the active state


    A competitive antagonist binds equally tightly to the ‘inactive’ and active states of the receptor: No change in equilibrium


    A partial agonist binds to both the ‘inactive’ and ‘active’ states of the receptor: Partial shift of equilibrium


    Multiple receptor states: How to understand inverse agonists(in this LESS SIMPLE case, the receptorhas spontaneous (often called constituitive) activity in the absence of added drug)


    The less simple case: Some receptors are ‘active’ even in the absence of added drug


    Inverse agonists bind more tightly to the resting state of the spontaneously active receptor: Equilibrium shifts toward the inactive state


    Receptor activation by agonists, inverse agonists, etc.

    Newman-Tancredi et al., 1997


    How to quantify drug antagonism

    • Schild Equation

      • (C’/C) = 1 + ([I]/Ki)

  • Schild plot or Schild regression

    • log(C’/C - 1) vs. log [I]

  • pA2 = -log([I] giving a dose ratio of 2)

  • Where [I] = Kd of antagonist at its receptor.


  • Antagonism of acetylcholine by atropine

    Adapted from Altiere et al., 1994


    Schild plot of antagonism of acetylcholine by atropine

    Adapted from Altiere et al., 1994


    Antagonism of acetylcholine by pirenzepine

    Adapted from Altiere et al., 1994


    Schild plot: Antagonism of acetylcholine by two different antagonists

    3

    atropine

    pirenzepine

    2

    1

    0

    -6

    -5

    -10

    -9

    -8

    -7

    log [antagonist] (M)

    Adapted from Altiere et al., 1994


    DifferentpA2 values (affinities)for different receptors of some clinically useful drugs:The basis of therapeutic selectivity


    Evidence for the existence of spare receptors


    How nature achieves neurotransmitter sensitivity without a loss of speed: Spare receptors:


    Drug(D) - Receptor (R) Interaction

    k1

    D + R

    DR

    k2

    Kd = ([D] * [R]) / [DR] = k2/k1

    Kd = dissociation constant

    k1 = association rate constant

    k2 = dissociation rate constant


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