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PHRM 501 > Exam 2- Drug Target Interactions Part 2 > Flashcards

Exam 2- Drug Target Interactions Part 2 Flashcards

1
Q

Biochemistry- A receptor

A

A molecule that transduces a signal

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2
Q

5 classes of receptors

A
  1. Nuclear Hormone Receptors
  2. enzyme linked receptors
  3. enzyme associated receptors
  4. ligand gated ion channels
  5. 2nd Messenger systems (GPCRs)
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3
Q

Nuclear Hormone Receptors

A

act via intracellular receptors and the drug must cross the cell membrane

  • effects can last for hours or days after drug is gone
  • Beneficial and adverse effects last longer than drug elimination
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4
Q

Example of Nuclear Hormone Receptors

A
  • Growth hormones
  • Steroids like glucocorticoids, sex steroids, thyroid hormones
    Most common MOA: binding to DNA via response elements
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5
Q

Enzyme linked receptor

A

Large transmembrane proteins with extracellular ligand binding domains and intracellular enzyme domains
- common with trophic hormones like insulin

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6
Q

Enzyme linked receptor signaling events

A
  1. ligand binds extracellular domain
  2. conformational change
  3. dimerization (homo- or hetero-)
  4. kinase domains together
  5. phosphorylation event
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7
Q

Example of Enzyme linked receptor

A

Receptor tyrosine kinase

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8
Q

Ligand induced dimerization and phosphorylation

A

leads to variety of signaling events triggered
- further effects downstream events like
1. altering membrane permeability to ions
2. changes in gene expression
3. increased nutrient transport and more
intensity and duration of agonist-activation limited by receptor down-regulation

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9
Q

Dimerization may vary

A

depending upon ligand or cell type

- doesn’t happen until ligand binding

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10
Q

Intensity and duration of agonist-activation is limited by

A

receptor down regulation

  • ligand binds, receptor endocytose and degraded
  • New R synthesis takes time, limits drug efficacy
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11
Q

Enzyme Associated Receptor

A

Mechanism of action is similar to kinase receptors, but, kinase activity is not intrinsic to the receptor - external molecule mediates phosphorylation
Ex. JAK/STAT pathway

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12
Q

Cytokines

A

large class of molecules that mediate cell-cell communication, particularly involving the immune system

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13
Q

For enzyme associated receptors Activity remains

A

as long as receptor is dimerized- even if ligand is gone

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14
Q

Ligand-gated ion channel

A
  1. ligand binds receptor, opens channel, ions flux down (electro)chemical gradients
    - Ion channels are not all the same multiple subtypes
    - the ligand binding site is on the extracellular surface
    - Effects are turned off immediately once ligand is gone
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15
Q

Second Messenger Systems

A
  • most complicated of the receptor systems
  • lead to great signal amplification
  • part of signal transduction pathways,
  • GPCRs: signaling in 3 parts
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16
Q

3 Parts of G protein Coupled Receptors

A
  1. extracellular ligand binds to specific receptor
  2. G-protein activated on cytoplasmic/intracellular surface (exchanges GDP for GTP)
  3. G-protein changes activity of some effector like enzyme or ion channel
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17
Q

G-proteins

A

family of proteins that function as molecular switch and an intermediate

  • can be more than one per receptor
  • bind and hydrolyze GTP, allows for tremendous signal amplification and increased longevity
  • can be both stimulatory and inhibitory
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18
Q

G-proteins are active while

A

bound to GTP

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19
Q

G-proteins are inactive while

A

bound to GDP

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20
Q

7TM

A

7 transmembrane loops

example of GPCR

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21
Q

cAMP

A

Cyclic adenosine monophosphate

  • made by adenylyl cyclase
  • example of various second messengers
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22
Q

cAMP what does it do

A

Mediates hormonal responses

  • renal water conversation
  • calcium homeostasis
  • production of hormones
  • smooth muscle relaxation (not skeletal muscle)
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23
Q

Phosphoinisotol (IP3)

A
  • example of 2nd messengers

- G-proteins stimulate phospholipase C which promotes the catabolism of membrane-bound PIP2 into DAG and IP3

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24
Q

IP3 diffuses through

A

the cytoplasm, binds calmodulin and cascades further

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25
Q

Gs proteins (Stimulatory)

A

Adenylyl cyclyase -> increased cAMP

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26
Q

Gi1, Gi2, Gi3 effector

A

Adenylyl cyclyase -> decreased cAMP

27
Q

Gq effector

mACh, bomesin, 5-HT2

A

Phospholipase C-> increased IP3

28
Q

Steps of GPCR

A
  1. Ligand binds to receptor
  2. G-protein is released from the receptor
  3. G-protein binds to the effector protein
  4. Change in 2nd messenger
  5. G-protein hydrolyzes GTP to GDP
29
Q

Nuclear hormone receptor response time

A

Slow (hours

30
Q

Nuclear hormone receptor - how the signal is transduced

A 
Gene transcription (upregulation or downregulation)
- induces a change in gene expression
31
Q

Nuclear hormone receptor - mechanism

A

Ligand binding results in conformational shift and binding to DNA response elements. Ligand must cross cell membrane

32
Q

Nuclear hormone receptor - Can the signal outlast the message?

A

Yes

33
Q

Ligand gated ion channel - how the signal is transduced

A

changes in ion transport

34
Q

Ligand gated ion channel - response time

A

Very rapid (milliseconds)

35
Q

Ligand gated ion channel - mechanism

A

Ligand opens or closes an ion channel. Typically extracellular binding of ligand

36
Q

Ligand gated ion channel - examples

A

Nerves, skeletal muscles

37
Q

Ligand gated ion channel - Can the signal outlast the message?

A

No

38
Q

Enzyme-coupled and enzyme-associated receptors - how the signal is transduced

A

Intracellular enzyme

39
Q

Enzyme-coupled and enzyme-associated receptors - response time

A

Moderate (minutes)

40
Q

Enzyme-coupled and enzyme-associated receptors - mechanism

A

Extracellular ligand binding results in intracellular enzymatic activity. Typically requires dimerization. Signal can be maintained after ligand leaves

41
Q

Enzyme-coupled and enzyme-associated receptors - examples

A

Response to cytokines, growth hormones

42
Q

Enzyme-coupled and enzyme-associated receptors - can the signal outlast the message?

A

Yes

43
Q

GPCR - how the signal is transduced

A

Second messenger (usually IP3 or cAMP)

44
Q

GPCR - response time

A

Rapid (seconds)

45
Q

GPCR - Mechanism

A

Extracellular binding to 7-TM results in activation of a GTP-binding protein. Activated G-protein goes on to activate some effector

46
Q

GPCR - Examples

A

Taste, smell, endocrine signals

47
Q

GPCR - can the signal outlast the messenger?

A

No

48
Q

Drug-Receptor complex formation leads to intracellular effector molecule phosphorylation

A

Receptor Dimerization and enzyme activation

49
Q

Which is a typical response to a G-protein activation?

A
  • Activation of phospholipase C
  • activation and inhibition of adenylyl cyclase

-NOT involved in inhibition of phospholipase C

50
Q

Membrane permeability of the ligand is most imporant for which type of receptor

A

Nuclear Hormone receptor bc it has to cross the cell membrane

51
Q

Which type of receptor frequently uses protein phosphorylation to tranduce its signal?

A

Enzyme linked receptor

52
Q

Within living systems, EC50 is

A

a measurement of a biological response of a compound

53
Q

The bigger the therapeutic window

A

the better and more safe we consider the drug to be

54
Q

A low EC50 means

A

high therapeutic window

55
Q

ED50

A

dose at which 50% of patient population exhibits specific effect
- effective dose, 50% of population
agonist activation

56
Q

TD50 and LD50

A

toxic and lethal doses for 1/2 the population
TD is used more than LD
TD50- measure of toxicity

57
Q

NOAEL

A

No observed adverse events level

58
Q

Drug selectivity confers

A

utility, clinically

selectivity is a major factor during drug development as target specific, or receptor specific binding

59
Q

Tied to the same R and effector

A
  • on target toxicity
  • Usually a dose response, optimal dose to “fix” pathological condition
  • too much drug exaggerates E
    Ex: Diabetes type 1 use of insulin: if overdose -> hypoglycemic coma
60
Q

Mediated by the same R on different cells/tissues

A
  • on target toxicity
  • same receptors exist on multiple cells, may differentiate Beneficial vs. Adverse R
    Ex: MOR in CNW vs. GI tract
61
Q

How to avoid/ mitigate for mediated on the same R

A
  1. Use lowest effective dose
  2. Effect pathology via administration of multiple drugs with different MOAs
  3. Targeted delivery ( concentrate drug at R for benefit)
62
Q

Mediated by different R

A
  • off-target toxicity
  • Drugs are selective not specific, so toxicities may be mediated by other receptor binding
  • Not always bad bc some new drugs/receptors have been discovered bc of these off target R bindings.
  • Its a problem and a potential opportunity
63
Q

Hypotension is an example of

A

on target toxicity

PHRM 501 (21 decks)

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