Receptor Pharm II Flashcards
Competitive Antagonist
Bind to receptor at SAME site as agonist
E/Emax of competitive antagonists
0
Agonist and antagonist binding sites may not be identical, but they are…
Mutually exclusive
Drug + Antagonist-Receptor Binding Equation
R + A + B RA + RB
KA equation
KA = [R][A]/[RA]
KB equation
KB = [R][B]/[RB]
Binding and effect equation for antagonist
(E/Emax) = [A]/(EC50(1+[B]/KB) +[A])
Antagonists shift the agonist curve to the _____, making the agonist _____ potent
Right, less
Magnitude of the shift caused by antagonist
1 + [B]/KB
When [B] = KB, agonist curve shifts by a factor of
2
Half-maximal inhibitory concentration of antagonist (IC50) is used to…
Compare potency of antagonist drugs
What does intrinsic efficacy (e) of agonists determine?
How well drug activates receptor when bound
Full agonist
Produces max (100%) response
Intrinsic efficacy of full agonists
High
Partial agonists
Do not produce max response even when occupying ALL receptor sites
Intrinsic efficacy of partial agonists
Low
Intrinsic efficacy equation
(E/Emax) ~ e • ([D]/(EC50 + [D])
Partial agonist is also known as _____. Why?
Partial antagonist; they block the remaining efficacy of the full agonist
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
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
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
Non-Competitive Antagonists
Cannot be surmounted by any concentration of agonist
Types of non-competitive antagonists
Irreversible - permanent covalently bound
Allosteric - reversible, prevents receptor activation when agonist is bound, but does not impact agonist binding
Therapeutic effect of non-competitive antagonists
Reduces agonist effect potency (EC50)
Shift curve right
KA is unchanged
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
