Receptor Pharm II Flashcards by Ari Strick

Competitive Antagonist

Bind to receptor at SAME site as agonist

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E/Emax of competitive antagonists

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Agonist and antagonist binding sites may not be identical, but they are…

Mutually exclusive

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Drug + Antagonist-Receptor Binding Equation

R + A + B RA + RB

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KA equation

KA = [R][A]/[RA]

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KB equation

KB = [R][B]/[RB]

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Binding and effect equation for antagonist

(E/Emax) = [A]/(EC50(1+[B]/KB) +[A])

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Antagonists shift the agonist curve to the _____, making the agonist _____ potent

Right, less

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Magnitude of the shift caused by antagonist

1 + [B]/KB

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When [B] = KB, agonist curve shifts by a factor of

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Half-maximal inhibitory concentration of antagonist (IC50) is used to…

Compare potency of antagonist drugs

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What does intrinsic efficacy (e) of agonists determine?

How well drug activates receptor when bound

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Full agonist

Produces max (100%) response

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Intrinsic efficacy of full agonists

High

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Partial agonists

Do not produce max response even when occupying ALL receptor sites

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Intrinsic efficacy of partial agonists

Low

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Intrinsic efficacy equation

(E/Emax) ~ e • ([D]/(EC50 + [D])

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Partial agonist is also known as _____. Why?

Partial antagonist; they block the remaining efficacy of the full agonist

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Why are some ligands agonists whereas others are antagonists?

Full agonists make all contact points on receptor
Partial agonists make some contact points on receptor
Antagonists don’t make any of the contact points, but occupy the pocket

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Therapeutic implications of partial agonists

Agonist or antagonist action depends on receptor activation
Some response will always be present
Antagonist action prevents response from being over-activated by other endogenous ligands

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Examples of partial agonists

Beta blocker with partial activator activity to ensure adequate resting HR… but prevents HR from increasing too much with exercise/stress

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Non-Competitive Antagonists

Cannot be surmounted by any concentration of agonist

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Types of non-competitive antagonists

Irreversible - permanent covalently bound

Allosteric - reversible, prevents receptor activation when agonist is bound, but does not impact agonist binding

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Therapeutic effect of non-competitive antagonists

Reduces agonist effect potency (EC50)
Shift curve right
KA is unchanged

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What happens when all the spare receptors are depleted?

Curve shifts down

Action duration for irreversible inhibitors. Why?

Days to weeks; cell has to synthesize new receptors

Allosteric modulators

Bind to secondary (Allosteric) binding site

What do Allosteric modulators need to have action?

Endogenous ligands present

Impact of binding at Allosteric site

Alters agonist binding at orthosteric/primary site

Positive modulators

Increase actions/effects at primary site

Negative modulators

Decease actions/effects at orthosteric/primary site

Example of Allosteric modulators

Benzos

Functional Antagonists/Physiological Antagonism

Agonist with opposing functional effect appears to act like antagonist of each other even though they bind to different receptors

Functional Antagonist/Physiological Antagonism Example

ACh on muscarinic receptor causes vasodilation as a result of vasoconstriction caused by norepi acting on alpha-1 adrenergic receptor

Ligand-Gated Ion Channel Receptor prototype

Nicotinic acetylcholine receptor

Ligand-Gated Ion Channel Receptor: endogenous ligand and agonist drug

Endogenous ligand - acetylcholine | Agonist drug - nicotine

Ligand-Gated Ion Channel Receptor: effect of agonist binding and response

Channel opens and sodium enters cell, causing depolarization Response - muscle contraction

Ligand-Gated Ion Channel Receptor: Time frame

Milliseconds

GPRC: prototype and endogenous ligands

Beta-adrenergic receptor | Endogenous ligands - epi and norepi

GPCR: agonist drug

Isoproterenol (cardiac stimulant)

GPCR: effect of agonist binding and response

Binding - activated GTP-binding proteins that regulate enzymes in turn to generate 2nd messenger molecules Response - metabolism, secretion, smooth muscle contraction/relaxation, cell migration, etc.

GPCR: time frame

Seconds to minutes

Receptors with Intrinsic Enzyme Activity: prototype

Insulin receptor

Receptors with Intrinsic Enzyme Activity: endogenous ligand and agonist drug

Endogenous ligand & agonist drug: insulin

Receptors with Intrinsic Enzyme Activity: effect of binding and response

Binding - activates enzymatic activity (tyrosine kinase) of intracellular domain Response - gene expression, cell growth and differentiation, cancer cell growth

Receptors with Intrinsic Enzyme Activity: time frame

Minutes to hours (long-lasting)

Intracellular Transcription Factor Receptors: prototype

Estrogen receptor

Intracellular Transcription Factor Receptors: endogenous ligand & agonist drug

Estradiol

Intracellular Transcription Factor Receptors: effect of binding and response

Binding - causes receptor to trans locate and bind to DNA response elements, regulating gene transcription Response - gene expression, cell growth and differentiation, cancer cell growth

Receptor Subtypes

Different receptor proteins for the same endogenous ligand Typically numbered to differentiate Endogenous ligands act on multiple receptor subtypes

Endogenous ligands are ________ agonists because they activate multiple subtypes

Non-selective

Which drug tends to have fewer side effects?

Selective drugs

Key differences among Subtypes

Expressed differently in various tissues | Coupled to different signaling pathways that mediate different effects

Beta agonist/antagonist example

Beta 2: agonist for asthma but not HR/BP | Beta 1: antagonist for angina but not airway constriction

G proteins signaling pathway examples

Beta-adrenergic couples to Gs and increases cAMP | Alpha-1 adrenergic couples to Gq and regulates Ca

Repeated exposure to agonists lead to…

Modifying/phosphorylating receptor so it is removed and degraded

Down-regulation

Removal of receptors so they no longer interact with agonists

Tolerance/tachyphylaxis

Loss of responsiveness to drug effects

What happens to ligand-gated ion channels if agonist occupancy is too long?

Desensitized/blocked

What does repeated exposure to antagonists cause? What is this called?

Increased # of receptors to interact with agonists | Up-regulation

Clinical implication of down-regulation

Increased agonist dose May be needed to maintain therapeutic effect

Clinical implication of up-regulation

Abrupt discontinuation of antagonist may cause life threatening rebound effect when agonist action is restored