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Medicinal Chemistry > Lecture 6 - Drug Targets > Flashcards

Lecture 6 - Drug Targets Flashcards

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1
Q

What are receptors responsible for?

A

Transmitting a signal to a cell

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2
Q

What occurs in voltage-gated ion channels?

A
  • Depolarization causes opening of ion channel
  • Ions pass through
  • Hyperpolarization causes closure of ion channel
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3
Q

What occurs when a drug binds to an ion channel?

A

Typically inhibits its function

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4
Q

Where can drug binding occur on an ion channel?

A
  • Intracellular or extracellular part

- Can be w/in the pore of the channel itself or on the outside

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5
Q

Where and when drug binds to an ion channel depends on _____

A

The ion channel and the drug

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6
Q

What are some examples of drugs that bind to ion channels?

A
  • Local anesthetics (sodium ion channel blockers)
  • Calcium channel blockers
  • Class 1 and 2 antiarrhythmics
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7
Q

How are ligand gated ion channels opened?

A

Binding of agonist to ion channel

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8
Q

Where does receptor binding normally occur in ligand gated ion channels?

A

Outside of membrane

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9
Q

What are some examples of ligand gated ion channels?

A
  • Nicotine
  • Acetylcholine
  • GABAa
  • AMPA receptors
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10
Q

Nicotinic acetylcholine receptor requires ____ ligands

A

2

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11
Q

What occurs in nuclear hormone receptors?

A
  • Hormone enters nucleus and binds to nuclear hormone receptor
  • Complex binds to response element of DNA
  • Causes a change in mRNA expression => change in protein production and tissue response
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12
Q

What does a ligand bind on a nuclear hormone receptor and what does this cause?

A
  • Ligand binds to ligand binding domain (AF-2)
  • This causes a conformational change in receptor, which then causes a conformational change in the DNA binding domain (AF-1), which allows it to bind to DNA
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13
Q

What are some examples of ligands for nuclear hormone receptors?

A

Nuclear hormone like sex steroids or glucocorticoids

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14
Q

What is the receptor for estradiol?

A

Estrogen receptor

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15
Q

What is the receptor for testosterone?

A

Androgen receptor

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16
Q

What is the receptor for progesterone?

A

Progesterone receptor

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17
Q

What is the receptor for cortisol?

A
  • Main receptor - glucocorticoid receptor

- Other receptor - mineralocorticoid receptor

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18
Q

What is the receptor for aldosterone?

A
  • Main receptor - mineralocorticoid receptor

- Other receptor - glucocorticoid receptor (weak)

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19
Q

What is the binding of cortisol to mineralocorticoid receptor considered?

A

Off-receptor effect

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20
Q

What occurs in the estrogen receptor?

A
  • Estradiol passively diffuses across cellular membrane and nuclear envelope
  • Receptor dimerizes and binds to estrogen receptor alpha, which then binds to estrogen response element of DNA
  • Causes a change in mRNA expression => protein and tissue response changes
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21
Q

What are transmembrane enzymes?

A

A group of receptors that have an extracellular ligand binding domain and an intracellular enzymatic domain w/in the same protein

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22
Q

What are 2 examples of transmembrane enzymes?

A

1) Epidermal growth factor
2) Insulin receptors
- Contain intrinsic tyrosine kinases in cytoplasmic domain

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23
Q

What are the ligands for the EGF receptor?

A

EGF or transforming growth factor alpha

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24
Q

Overgrowth of EGF receptors is found in ____

A

Epithelial cancers

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25
Q

What is the function of the EGF receptor?

A

Several signal transduction cascades leading to DNA synthesis and cell proliferation of epithelial cells

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26
Q

What occurs in the EGF receptor?

A
  • Ligand binds causing EGFR dimerization and tyrosine kinase activity
  • This leads to autophosphorylation of several EGFR tyrosine residues, causing activation of signal transduction cascades => DNA synthesis and cell proliferation
27
Q

What does phosphorylated tyrosine act as in the EGFR?

A

A signal

28
Q

What is an antagonist for an enzyme?

A

Inhibitor

29
Q

What some important endogenous ligands for GPCR’s?

A
  • Adrenaline / noradrenaline
  • Acetylcholine
  • Serotonin
  • ADP
  • Dopamine
  • Histamine
  • Glutamate
  • Peptide hormones
30
Q

What are the 3 components of GPCRs?

A

1) Receptor on outside of membrane binds ligand
2) G-protein on inside of membrane senses signal from ligand receptor interaction
3) 2nd messenger propagates signal throughout cell

31
Q

What does an effector protein do?

A

Binds G-protein and produces or inhibits production of 2nd messenger

32
Q

What is a GPCR composed of?

A

7 alpha helices that cross the membrane (also called transmembrane helix receptors)

33
Q

Where is the ligand receptor of a GPCR located?

A

Extracellular side

34
Q

Why is it called a G-protein?

A

Binds to GTP

35
Q

Where is the signalling protein of a GPCR located?

A

Intracellular side

36
Q

What is the function of a G-protein?

A

Transmit signal from receptor-ligand complex into the cell through biochemical cascade

37
Q

Can one receptor activate only one G protein?

A

No, can activate multiple G-proteins

38
Q

What happens to the GPCR after a ligand binds?

A

Affinity for GDP decreases and affinity for GTP increases

39
Q

What happens after GTP binds to a GPCR?

A
  • Dissociation of G alpha and G beta-gamma, which then interact w/ respective effector proteins
  • G alpha hydrolyzes GTP to GDP and hydrolysis results in re-association of G alpha and G beta-gamma, eliminating signal
40
Q

What does G alpha s do?

A

Activates adenylate cyclase => opens Ca2+ channels leading out of the cell

41
Q

What is the 2nd messenger of G alpha s?

A

cAMP (produced)

42
Q

What does G alpha i do?

A

Inhibits adenylate cyclase and opens K+ channels

43
Q

What is the 2nd messenger of G alpha i?

A

cAMP (inhibited)

44
Q

What does G alpha q do?

A

Activates phospholipase C beta

45
Q

What is the 2nd messenger of G alpha q?

A

DAG and IP3 (produced)

46
Q

What does Go do?

A

Activates receptors that inhibit Ca2+ channels leading out of cell

47
Q

What does cAMP do?

A

Binds to and activates protein kinase A

48
Q

What does protein kinase A do?

A

Phosphorylates many target proteins that amplify the signal again and produce many coordinated responses

49
Q

What extinguishes the signal from cAMP and how?

A
  • Phosphodiesterase

- By hydrolosing it into 5’AMP which does not bind to PKA

50
Q

The active site of adenylate cyclase is blocked until ____

A

G alpha s binds

51
Q

What needs to be bound to adenylate cyclase for it to produce cAMP?

A

G alpha s

52
Q

What does G alpha s have intrinsic activity of and what does this mean?

A
  • Has GTPase intrinsic activity

- Deactivates itself

53
Q

What occurs when protein kinase A is stimulated through G alpha S?

A

A cascade of effects are initiated that liberate energy sources from storage and prevent storage of energy sources

54
Q

What happens when membrane bound adenylate cyclase binds G alpha i?

A

Adenylate cyclase is inhibited and no cAMP is produced

55
Q

Does G alpha i produce an inhibitory effect by itself?

A

No, with G beta-gamma subunits which open K+ channels, causing hyperpolarization of membrane

56
Q

What does phospholipase C beta do once activated?

A

Hydrolyzes phosphatidylinositol diphosphate (PIP2) into the 2nd messengers DAG and IP3

57
Q

Where is PIP2 found?

A

In membrane

58
Q

Do DAG and IP3 leave the membrane?

A
  • DAG is hydrophobic so stays in the membrane

- IP3 is hydrophilic, so it diffuses into cytosol

59
Q

Do G alpha s and G alpha q have the same effect?

A

No, G alpha q counteracts the signal from G alpha s

60
Q

What also happens after G alpha q binds to phospholipase C beta (besides PLC beta being activated)?

A
  • Intracellular Ca2+ increases in smooth muscle causing contraction
  • Ca2+ binds to calmudolin and stimulates PDE, which hydrolyzes cAMP to 5’AMP
61
Q

What is the net effect of G alpha s?

A

To decrease intracellular Ca2+, which counteracts the effects of G alpha q

62
Q

Can one GPCR activate only one G-protein?

A

No, can activate multiple

63
Q

Does one G-protein have only one effector protein?

A

No, can have multiple

Medicinal Chemistry (14 decks)

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