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Pharm > Lecture 2: How Drugs Bind to their Targets > Flashcards

Lecture 2: How Drugs Bind to their Targets Flashcards

1
Q

What are modes of signal transmission?

A

Common mechanisms by which receptors interact with drugs and generate a signal in the cell which causes a biological response

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2
Q

How can a drug get to intracellular recptors?

A

Because the receptor is on the inside of the cell, the drug has to cross the membrane in order to get to the receptor

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3
Q

What properties must the drugs that target intracellular receptors have?

A

They must be lipid soluble (hydrophobic) or have some other transport mechanism in order to cross the cell

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4
Q

What are examples of drugs that can bind to intracellular receptors?

A

Steroid hormones: Glucocorticoids, anabolic steroids etc

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5
Q

What is the Mode of Action of substances that bind to Intracellular Receptors?

A

They bind to the Ligand binding Domain (LBD) of a steroid hormone receptor, leading to the displacement of the Heat Shock Protein (HSP) or other chaperone. This exposes a DNA recognition domain and leads to the activation of transcription target genes

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6
Q

What is the relative timing of intracellular receptors?

A

Its effects typically have slow onset and are long lasting (not rapidly reversible)

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7
Q

Why is the relative timing of Intracellular receptors slow?

A

Because it requires transcription and gene synthesis

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8
Q

What kind of receptors are G-protein coupled receptors (GPCRs)?

A

Transmembrane receptors

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9
Q

Which side do ligands bind to on G-protein coupled receptors?

A

They bind to the extracellular side

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10
Q

What generally happens once ligands bind to the extracellular side of GPCRs?

A

The ligand triggers a conformational change that activates a signaling cascade mediated by intracellular G-proteins

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11
Q

What are the G-proteins distinct from?

A

The receptor

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12
Q

What does the activation of the receptor do in G proteins?

A

Promotes the exchange of GDP for GTP

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13
Q

What is meant by the G-alpha subunit has GTPase activity?

A

It acts like a molecular timer or countdown to terminate the signal and hydrolyzed GTP to inactivate the G-protein complex

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14
Q

What can active G-proteins do?

A

Influence effector proteins that alter cellular activity

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15
Q

What are the three intracellular G-proteins that a receptor is coupled with?

A
  • G-alpha
  • G-beta
  • G-gamma
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16
Q

What is G-alpha bound to at rest?

A

GDP

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17
Q

What happens once G-alpha binds to GTP?

A

It dissociates from the G-protein complex and acts as an effector

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18
Q

When a receptor is activated what do the G-beta and G-gamma subunits usually stay associated with?

A

The membrane

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19
Q

What can the G-beta and gamma subunits do?

A

They can directly activate various downstream effectors like ions channels or recruitment of kinases

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20
Q

What are the three types of G-alpha subunits?

A
  • Gs
  • Gi
  • Gq
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21
Q

What can the different types of G-alpha do?

A

Influence different signalling cascades

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22
Q

What are the two main targets of the alpha subunit of G proteins?

A

Adenylate cyclase (AC) and phospholipase C (PLC)

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23
Q

What does the Gs type of alpha subunit do?

A

Activates Adenylate Cyclase

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24
Q

What does the Gi type of Alpha subunit do?

A

Inhibits Adenylate Cyclase

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25
Q

What does the Gq type of the G-alpha subunit do?

A

It activates Phospholipase C (PLC)

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26
Q

What is the distinction between the effects of the G-beta and G-gamma subunits versus the G-alpha subunits?

A

The G-beta and G-gamma subunits have direct effects on the effector and the G-alpha components have effects of the initial components of the signalling cascade

27
Q

How does Gs work? (Explain what happens from Gs dissociation)

A

Receptors coupled to Gs trigger increased activity of AC which converts ATP to cyclic AMP (cAMP), which activated cAMP dependant protein kinases like protein kinase A (PKA). PKA which phosphorylates substrates using ATP

28
Q

How does Gi work?

A

It suppresses the activity of AC which suppresses the production of cAMP

29
Q

What is the relative timing of G-protein coupled receptors?

A

They can happen very quickly

30
Q

How does Gq work?

A

Receptors coupled to Gq trigger increased activity of PLC, leading to production inositol triphosphate (IP3) and DAG from the breakdown of PIP2. IP3 triggers the release in intracellular Ca2+ stores which can influence other signalling pathways.

31
Q

Aside from IP3 what is the other product of PIP2 breakdown by PLC?

A

DAG

32
Q

What does DAG from the breakdown of PIP2 do?

A

Activation of protein kinase C and target substrates

33
Q

What activates protein kinase C?

A

DAG

34
Q

What is activation of Tyrosine Kinase Receptors TKRs driven by?

A

Dimerization of receptors in the presence of a ligand

35
Q

What does the dimerization of TKRs in the presence of a ligand do?

A

Cause them to autophosphorylate and become activated

36
Q

What is the difference between G-protein coupled receptors and TKRs?

A

TKRs have protein kinases built into them whereas G-protein receptors have multiple steps to activate protein kinases

37
Q

What is the circulating form of drugs that can bind to intracellular receptors?

A

Bound to carrier globulin because of low solubility in plasma

38
Q

What is the speed of response of intracellular receptors and why?

A

Slow because they require DNA binding and activation for target genes

39
Q

What is the Speed of Response of cell surface receptors and why?

A

Fast because of rapid transduction via protein conformational change and intracellular signalling cascades

40
Q

What is the speed of the the Breakdown or Termination of a cell surface receptor signal and why?

A

Fast because a signal can rapidly terminate due to rapid GTPase cycle

41
Q

What is the speed of the the Breakdown or Termination of a intracellular receptor signal and why?

A

Slow because a large fraction of a hormone is bound and there is usually a large reserve and effects of gene expression are slow to reverse

42
Q

What does the fastest mechanism of signalling in the body depends on?

A

Electrical signals generated by ion channel proteins

43
Q

What do Ion Channels do?

A

Allow ions to cross the membrane rapidly leading to changes in membrane voltage

44
Q

What can different ion channels be controlled by?

A

Distinct stimuli like a ligand binding or changes in a membrane voltage

45
Q

How do voltage gated ion channels respond to changes in voltage of the membrane?

A

Amino acids in the transmembrane electric field change position in response to changes in voltage

46
Q

What do common drugs for psychiatric conditions target?

A

Ligand gated channels

47
Q

What are other common drug targets?

A
  • Structural proteins
  • DNA replication machinery (foreign or native)
  • Membrane transport proteins
  • Enzymes
  • Foreign proteins
48
Q

What does Agonism mean?

A

A substance /drug binds to a receptor and influences its activity

49
Q

What is Agonism usually depicted in?

A

A concentration response curve

50
Q

What is EC50: Effective Concentration 50?

A

The concentration of a drug that yields 50% maximal effect

51
Q

What is Emax?

A

The maximal biological effect observed with the drug

52
Q

What is Efficacy?

A

A term that refers to the maximal drug effect (Emax)

53
Q

What is Potency?

A

A term that refers to the concentration dependence (EC50)..

54
Q

How would you describe a drug that has a high Emax?

A

It has a high efficacy

55
Q

What would be the characteristics of a drug that has a high potency?

A

It has a small EC50

56
Q

What will Potency and Efficacy always refer to?

A

Potency refers to drug concentration and Efficacy refers to drug effect

57
Q

What do drugs with different potency exhibit?

A

Difference concentration required for a particular effect

58
Q

What do drugs with difference efficacy exhibit?

A

A difference in the maximal effect that can be achieved

59
Q

What are Agonists usually categorized by?

A

Their efficacy

60
Q

What are the four types of Agonists?

A
  • Full agonist
  • Partial agonist
  • Antagonist
  • Inverse agonist
61
Q

What does a Full agonist do?

A

Binds to a receptor and generates the maximal observed effect

62
Q

What does a Partial Agonist do?

A

Binds to a receptor and generates a fraction effect

63
Q

What CAN’t Antagonist do?

A

Generate a biological effect on their own

64
Q

What do Inverse Agonists do?

A

Cause suppression of basal activity of a receptor

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