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MedChem Midterm 3 > Receptors 1 > Flashcards

Receptors 1 Flashcards

1
Q

Receptor

A
  • Refers to a protein that participates in intracellular communication via chemical signals
    • Upon recognition/binding of external chemical signal (ligand)
      • Receptor protein transmit signal INSIDE the cell.
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2
Q

Receptor Lignads

A
  • Include Endogenous signaling molecules:
    • Hormones
    • Neurotransmitters
  • Also Include Drugs that serve as antagonist or agonist.
    • Ex.
      • Propranolol antagonizes #> b-adrenergic receptors
      • Prazosin antagonizes #> a-adrenergic receptors
      • Atropine #> AcTH on cholinergic muscarinic receptors
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3
Q

Signal Transduction

A
  • Process of transferring the information from:
    • OUTSIDE the cell –> to inside the cytoplasm​
  • ​First messenger (ligand/drug) concentration levels are translated into a biological response
    • = secondary messenger
    • Most signaling across membranes occur by one of a limited set of mechanisms
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4
Q

Signal Transduction Mechanisms

5

A
  • Lipid-soluble drug diffuses across the membrane
    • –> intracellular receptor (enzyme / regulatory protein)
  • Drug binds to transmembrane ion channel
    • stimulates internal enzyme action
    • 2 forms - simply converting or phosphorolating
  • Drug binds to transmembrane ion channel
    • regulates its opening (can be in or out)
  • Drug binds to cell-surface receptor
    • –> interacts with G-protein
      • –> regulates an internal enzyme activity
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5
Q

Ligand Gated Ion Channels

LGIC

A
  • Binding –> ions enter
    • change in membrane potential
    • ionic concentration change
  • VERY FAST
    • ​if the effect of the ligand is conformational change of the receptor
      • GABAAR / AChR / Nicotinic acetylcholine
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6
Q

Tyrosine Kinase Linked Recptors

TRKs

A
  • binding –> protein phosphorolation
    • ​ex. Insulin receptor
  • _​_response is slower
    • since a reaction is required (phosphorolation)
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7
Q

G-Protein Coupled Receptors

GPCRs

A
  • binding of cell-surface receptor–> g-protein –>
    • intracellular secondary messenger (cAMP)
      • –> protein posphorlation (does not always occur)
    • ​​​ex. B-adrenergic receptor
  • _​_slower due to reaction required (phosphoralation)
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8
Q

Ligand Activated Transcription Factors

eg. SERMs

A
  • ligand –> intracellular receptor
    • ​–> translation / transcription
    • –> protein –> effect
  • takes hours, takes the longest time for effects
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9
Q

Nicotinic AcetylCholine Receptor

A

Ligand Gated Ion Channel (LGIC - Na/K)

  • ACh Binding –> rotation of transmembrane helices
    • ​(M2 amphipathic helixes surround the channel)
    • ​–> OPENING of inner pore
      • allows sodium and pot. to go through
  • Ex. Varenicline (chantix)
    • ​partial AGONIST of 1 subtype of the receptor
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10
Q

Varenicline

Chantix

A

Partial Agonist

Nicotinic Acetylcholine Receptor

  • –> conformational change –> allows na/k to enter
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11
Q

Volted Gated Ion Channels

VGIC

A
  • Comprised of a voltage sensor / pore / gate
  • Ion Specific
    • Na / K / Ca / Cl
  • Activated by changes in electrical membrane potential
    • ​Movement of voltage sensor
      • ​–> conformational change (open/close)
  • Critical role in excitable cells:
    • ​Neuronal / Muscle cells
  • ​Ex.
    • Verapamil (Ca channel blocker)
    • Amiodarone (arrhythmics)
    • Carbamezapine (Na)
    • Penytoin (Cl)
    • Lidocaine (anesthetics NA)
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12
Q

Transient Voltage (TRP-type) Ion Channels

ex. TRPV

A
  • 6 major types that differ in ligand specificity & bio fxn
  • Tetramers w/ 6 transmembrane helices in each
  • Most important for drugs:
    • TRPV (vanniloid)
    • TRPA (anykrin)
    • TRPM (melastatin)
  • also involved in INSECT VISION downstream from rhodopsin
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13
Q

Transient Voltage Ion Channels

TRPV1

A
  • Vanilloid receptor
    • Thermal / Noxious agent sensors
      • <activated by pungent chemicals:>
        <li>
        <strong>capsaisin</strong> / <strong>Resinferatoxin</strong>

</li>
<li>
<strong>DkTx (</strong>spider venom toxin) / vanillotoxin</li>
</activated>
* Analgesic drug design
* DUAL GATE MECHANISM
* 2 diff ligands bind in different region of receptor
* –> conformational changes induced by each ligand
* are allosterically coupled

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14
Q

Transient Voltage Ion Channels

TRPA

A = ankyrin

A
  • Ankyrin mechanoreceptor
    • ​activated by pungent chemicals:
      • wasabi: allyl isothiocyanate
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15
Q

Transient Voltage Ion Channels

TRPM

m = melastatin

A
  • Melastatin receptor
    • diverse fxn amoung 8 species:
    • cold sensors
      • < pepperment / menthol / calcium
  • ​​Overexpression –> tumorigenesis
    • ​= prostate cancer / melanoma
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16
Q

GPCRs

A
  • Lefkovits / Kobilka Nobel Prize
  • Large family of signaling proteins
    • each specifically binding a unique small-molecule ligand
  • Transduce chemical “signal” from OUTSIDE
    • –> internal changes (biological response)
  • Integral to plasma membrane
    • ​a-helixes transverse membrane
    • characteristic 7-helix bundle structure (7-pass)
    • extracellular domain = bind agonist
    • intracellular domain = regulate cytosolic enzymes__​
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17
Q

GPCR

Dopamine D3 Receptor

A
  • 7transmembrane helices (a) + extracellular loops
    • = form binding pocket for dopamine
    • ex. ETICLOPRIDE (D-receptor ANTAgonist)
  • ICL2 (intracellular helix)
    • –> conformational change after binding
      • assumes alpha-helical structure w/ 2-3 helical turns
    • communicates w/ G-proteins in the cell
      • –> activate enzyme (effector molecule)
  • Takes a longer response time compared to LGIC’s
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18
Q

Receptor Tyrosine Kinases

Insulin Receptor

IR

A
  • Agonist (insulin) –> IR –> Autophosphorylation
    • ​receptor aquires kinase activity
  • ​Phosphorolated receptor RECRUITS substrate (IRS1)
    • IRS1 is phosphorolated
      • –> binds to effector molecules = PI-3-kinase
      • ​​PIP3
        • ​–> transduce information to nucleus
  • longer response time needed to complete
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19
Q

Ligand-Activated Transcription Factors

ex. SERMs

A
  • Ligand (estrogen) –> ERbeta
    • –> binding to Major groove of DNA promoter region
      • DNA transcribed –> mRNA
        • translated –> variety of protein products
  • ex. myc / VEGF / Bcl2 / IGFR1 / IRS1/ TGFa / CD1
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20
Q

Allosteric Activator

A

Makes agonist effective at LOWER concentrations

Binding to allosteric site changes the affinity of the agonist site

  • less agonist is needed to exhibit response
  • bind to different (allo) sites
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21
Q

Allosteric Inhibitor

A

Makes agonist effective at HIGHER concentrations

Binding to allosteric site changes the affinity of the agonist site

  • MORE agonist is needed to exhibit response
  • bind to different (allo) sites
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22
Q

Lock & Key Model

A

Linus Pauling

  • ​Ligand = key
    • binds to specific receptor = Lock
      • ​​​–> unlocks cell response
  • First proposed by Emil Fishsher / JBS Haldane
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23
Q

Agonist

A
  • Drug = Agonist
    • Many drugs work by MIMICKING a natural ligand:
    • drug causes receptor to respond in the same way as the natural substance
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24
Q

Antagonist

A
  • ​Drug = Antagonist = Competitive inhibitor for enzymes
    • Bind to receptor @ Orthosteric binding site
      • and DO NOT produce a response
    • Prevent receptor from binding the natural ligand
      • # > inhibit function
      • ​this also counts for causing structure DEFORMATION that inhibits fxn
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25
Q

Dose-Response Curve

A

Fraction of Receptors Bound (B) Vs Drug Concentration (D)

  • Pysiological responses are NOT simple fxn of the amount of dose given
    • May be INITIALLY LINEAR
      • ​but level off @ higher doses
  • ​​Bmax = 100% of receptors bound
  • B IS NOT the same as effect or efficacy (vs EC50)
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26
Q

KD

A

Drug-Receptor Dissociation Constant

  • When drug cocentration (D) shows HALF SATURATION
    • ​[D] when [B = 50%]
      • ​half of receptors are occupied
  • Smaller the KD = Greater the affinity
    • ​less drug is needed to saturate the receptor
  • KD is related to the free energy of ligand-receptor interactions
  • not the same as EC50**​
  • inverse of Ka
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27
Q

Ka

A

Association Constant = AFFINITY

inverse of dissociation constant KD

Ka = k1 / k-1

  • Greater the Ka = greater the affinity
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28
Q

Semi-Logarithmic

Receptor Dose-Response Curves

A
  • Scale @ low concentration (where binding changes rapidly)
  • compresses [D] @ HIGH concentration (where binding changes slowly
  • Does not change value of Bmax & KD
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29
Q

Advantages of Semi-Log

Dose response curve

A
  • Better defined Plateau
  • Plotting of wide range of [D]
  • Enables comparison of drugs w/ different affinites due to compression of x axis
30
Q

Graded Dose Response Curve

Emax

ED50

A

Drug Efficacy [E] vs Drug Concentration [D]

  • Emax = maximum response (effect) achieved by agonist
    • = drug efficacy
  • ​ED50= druc conc. (dose) at which50% of Emax is achieved
    • ​= drug potency
  • different units of E vs B
31
Q

Drug Response Curves of Agonist

A
  • Agonist w/ High Affinity
    • ​shit curve to the LEFT
      • ​binding & drug action start @ LOWER concentrations of agonist
  • Agonist w/ LOW AFFINITY
    • ​causes curve to move to the RIGHT
      • ​MORE agonist is needed to make the drug-receptor complex
32
Q

Quantal Dose-Response Curve

A

Individuals Responsing (%) Vs Drug Dose [D]

  • Describe POPULATION rather than single individual responses
    • based on plotting comulative frequency of distribution of responsers
      • ​vs log of drug dose
  • Emax & ED50​​
    • ​like GRADED dose response curve
33
Q

Graded Response

A

INFINITE Number of intermediate stages

  • Blood vessel dialation
  • Bood Pressure Change
  • Heart Rate Change
34
Q

Quantal Response

A

BINARY all-or-none

  • Death
  • Pregnancy
  • Cure
  • Pain relief
  • Effect of a given magnitude
35
Q

Neutral Agonist

A

Have an efficacy of 0

Similar to Antagonist

bind to receptor without exerting an intracellular effect

36
Q

Types of Antagonism:

Pharmacological

A
  • blockage of the action of a drug-recepter interaction
    • by another compound
  • ex. cimetidine –> blocks interaction of:
    • histamine –> H2 Receptors
      • –> lower gastric acid secretion
37
Q

Types of Antagonism:

Physico-chemical

A
  • Interaction of two drugs in solution
    • such that the effect of the ​active drug is lost
  • ​​​Ex. metal chelators + toxic metals
38
Q

Types of Antagonism:

Biochemical

A

Agonist is DESTROYED by biochemical reaction

  • Ex. Sodium bicarb neutralizes Gastric acid secretion
  • Ex. Protamine antagonizes heparin
    • _​_protamine = alkaline w/ +e charge
    • heparin = acid w -e charge
39
Q

Types of Antagonism:

Physiological

A
  • Interaction of two drugs with opposing physiological actions
  • ​​Ex. Histamine vs Epinephrine
    • _​_Histamine LOWERS arterial pressure thru VASODILATION (h1 receptor)
    • Epinephrine RAISES arterial pressure thru VASOCONSTRICTION
      • ​B-adrenergic receptors
  • Ex. Insulin antagonizes gluticocorticoids
    • _​_hyperglycemic effects counteracted
40
Q

Pharmacological Antagonist:

Competative (surmountable) Antagonist

A
  • prevent biological actions of agonist
  • Bind to SAME SITE on receptor as agonist
  • inhibition CAN be overcome by increasing agonist concentration
    • = reversible
  • ​primarily affect agonist POTENCY
    • ​DO NOT alter receptor function
  • ​May also bind to another site on receptor that BLOCKS the action of an agonist
  • SHIFT RIGHT
41
Q

Pharmacological Antagonist:

Non-Competative (insurmountable) Antagonist

A
  • Bind Covalently to SAME SITE as agonist (IRREVERSIBLE)
  • ​or to a site distinct from that agonist (irreversible or reversible)
  • Inhibition CAN NOT be overcome by increasing agonist concentration
  • primarily affect EFFICACY
  • SHIFT DOWN
42
Q

Naloxone

A

u-opioid receptor ligand

COMPETATIVELY ANTAGONIZES

action of morphine / heroin

opiate overdose treament

43
Q

Perampanel

Fycompa, 2012

A

NONcompetative antagonist of AMPA

ionotropic glutamate receptor

Treatment of epilepsy (antiepileptic)

44
Q

Effect on Dose-Response Curves

Competative Antagonist

A

Agonist + Competative Agonist (B)

Agonist has REDUCED POTENCY

but still MAXIMUM EFFICACY

  • Produce a PARALLEL RIGHT-SHIFT
  • ​Magnitide of the shift is dependent on:
    • [B] , concentration of antagonist
    • KB , potency of antagonist
45
Q

Extent of Antagonism

A
  • Depends on the plasma concentration of the Antagonist:
    • dose of the antagonist
    • rate of clearance of the antagonist
    • ​​concentration of the agonist
      • ​–> can OVERCOME competative antagonist
  • prescription must take into account possible changes in the endogenous agonist concentration
    • ​ex. norepinephrine vs Propranolol
46
Q

Effect on Dose Response Curves:

Non-Competitive Antagonist

aka Allosteric / Allotopic

A

Agonist + Non-Competitive Antagonist

Agonist has Maximum Potency

but REDUCED EFFICACY

  • ​curve moves DOWN​ (depressed response)
    • ​no horizontal shift
47
Q

Glutamate

A

Allosteric Antagonist (modulator) Effect

modulator REDUCES mGlu1R signaling

DECREASES effect (shift down)

without effecting binding or potency (no lateral shift)

48
Q

GABA

A

Allosteric Antagonist (modulator) Effect

INCREASES Gaba POTENCY (<shift left<)

&

Maximal Effect (^shift up^)

49
Q

CP55940

full cannainoid receptor agonist

A

Allosteric Antagonist (modulator) Effect

DECREASES EFFICACY (moves down)

Increases Potency (moves left)

50
Q

Positive Allosteric Agonist of

GABA-AR

A

More Agonist Sites can be occupied

INCREASE maximal GABA response

  • Examples:
    • Etomidate / Neurosteroids
    • Barbiturates / Benzodiazapenes
    • Alcohols /Isoflurane / Propofol
51
Q

Propofol on GABA

A

Positive Allosteric Agent (propofol) on Gaba-ar

  • ​Receptor binds GABA more TIGHTLY
    • dose response curve shifts to the LEFT
  • ​@ particular GABA concentration, more agonist sites are occupied in the presence of propofol
    • response increases – shift ^^UP^^
52
Q

Occupancy Model

=

Two-State Model

A

Agonist occupies receptor –> Trigers Response

Strength of response : directly related to fraction of receptors occupied

does not explain all observations

53
Q

Two-Way Model

Occupency Model

A
  • DR*- Agonist binding –> conformational change
    • R->R* active
  • R* - Conformational change occurs SPONTANEOUSLY
    • in absense of agonist
      • –> is active
    • small fraction of R* is in EQ without athe agonist
      • agonist drives the conformational change, stabilizes R*
54
Q

Negatives/Shortfalls of

Occupency Model / Two-way model

A
  • Occupency model is INSUFFICIENT to explain these facts:
  • Experimentally shown:
    • Maximal response can be found when only a fraction of total receptor population is occupied
      • spare receptors are present
    • Diff. Drugs have different capacities to initiate response when bound
      • = different efficacies
    • ​Certain receptors are active even in absence of agonist
    • Certain drugs act as “inverse” agonist
      • shut down intrinsically active receptors​
55
Q

Relationship between

Occupancy & Physiological effect

A
  • assume that response (E) is :proportional: to receptor bound drug, ​where Emax = maximum effect
  • ​Magnitude of effect (E) is dependent on:
    • Drug Concentration [D]
    • Affinity KD (receptor occupancy)
    • Ability to activate the receptor “e”
      • ​aka intrinsic activity
56
Q

Potency Vs Efficacy

Curve

A

Potency INCREASE as response shift to the LEFT >>>

Efficacy INCREASES as maximal effects of receptor shift ^^UP^^

57
Q

Efficacy

A

Maximal Response produced by a drug

analogous to Maximal Velocity for Enzyme

  • Depends on 3 factors:
    • Intrinsic Activity (e)
    • Number of drug receptor complexes formed
    • Efficiency of signal transduction in producing physiological response
  • Possible to have High Affinity w/ low efficacy
    • or vice verse
58
Q

A?

A

FULL Agonist

Max Potency = lowest drug conc to reach max effect

Max Efficacy = reaches max effect

59
Q

B?

A

Partial Agonist

Maximum Potency = reaches it max potential

Reduced Efficacy = Is not as Effective as a full agonist

60
Q

C?

A

FULL Agonist

Reduced Potency = requires more drug to reach max efficacy

Maximum Efficacy = Reaches its full effect

61
Q

D?

A

Partial Agonist

  • Reduced Potency = requires more drug to be effective*
  • Reduced Efficacy = Is not as Effective as a full agonist*
62
Q

Partial Agonist

A

Agonist with efficacy <1 (e<1)

can serve as competitive agonist (also lower efficacy)

Shifts RIGHT! but can also shift down

  • May completely occupy receptor sites
    • BUT the response reaches a plateau at a value less than the maximal 100%
      • ​reduced effect SHIFT DOWN
  • ​​Agonist binding may favor new conformation of receptor
    • –> but has LESS intrinsic activity (lower efficacy)
    • = poor contact w/ “downstream” partners in signal path
      • ​or more receptor states may need to be considered
63
Q

Partial Agonist Vs Antagonist

A
  • Heroin = MOST efficacious agonist of opiod receptor
    • FULL AGONIST
  • Codeine** = most potent **partial agonist of opiod receptor
  • Nalaxone = antagonist
    • ​**effect of antagonist needs agonist to be present to be observed
      • ​otherwise silent
64
Q

Inverse Agonist

A

Has Independent impact upon receptor activity

produces Opposite effect to agonist

  • Unlike antagonist, they are active in the absence of agonist
    • intrinsically / constitutively active
  • ​Ex.
    • cimetidine –> H2 receptors
    • Haloperidol –> D2 receptors
65
Q

Quantitative Theory

Cheng-Prusoff Equation

A
  • Applicable to:
    • Simple Occupency model (esp. for enzyme INHIBITION)
    • Binding to Noncatalytic proteins (receptors)
  • Only consider competitive antagonism
  • KL = dissociation constant of AGONIST (ligand) used in displacement assay
    • obtained from literature / determined beforehand
  • {1 + [L]/KL} = Dose Ratio
66
Q

KD & EC50

A

​EC50 is ALWAYS HIGHER than KD

  • KD = thermodynamic paramater
    • interaction between receptor / antagonist
    • (absolute value / constant, like melting point)
  • EC​50 = functional strength of a ligand
    • ​depends on experimental conditions
      • ex. conc of L / presence of spare receptors
  • EC​50 would INCREASE if L was at a higher conc.
67
Q

KD = EC50 when?

A

if NO LIGAND IS PRESENT

when, [L] = 0

68
Q

ED50 Vs EC50

A

ED50 = DOSE for 50% of population to obtain therapeutic effect

Vs

EC50 = DOSE that reduces response to 50% of maximal value (invidual)

69
Q

Drug Potency

A
  • Expressed as the Dose or Concentration
    • that produces 50% of maximal response ED50 or EC50
      • ​under experimental conditions
  • ​​LOWER EC50 = GREATER Potency
    • ​less drug needed to produce same effect
70
Q

What effects EC50 ?

A
  • Affinity of drug for receptor KD
  • ​But also:
    • metabolism
    • distribution
    • Presence of other ligands
71
Q

KL

A

Dissociaition constant of AGONIST

used in displacement assay

Obtained from literature or determined beforehand

  • KD = dissociation constant of the receptor-antagonist complex
    • = affinity
72
Q

Fraction of Occupied Receptor

f

Receptor occupency “protein saturation”

A

Molar Fraction of occupied receptor

  • When [L] = KD, 50% protein is bound
  • When [L] = 0.1 KD only 9% of the protein is bound
  • When [L] = 10 KD, the protein is 91% saturated

MedChem Midterm 3 (7 decks)

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