Lecture 2 - Drug Targets Pharmacodynamics I

Question 1

________________ are inside the cells; drugs need to be able to cross the plasma membrane to interact with them.

Answer 1

Intracellular Receptors

Question 2

________ receptors must be ____ soluble to be able to cross the cell membrane

Answer 2

Intracellular; lipid

Question 3

What is an example of a ligand and their mode of action?

Answer 3

• Steroid hormones
• The receptor binds to the ligand/hormone and has a transactivating domain or a DNA binding domain which is masked by HSP90
• As the lipid soluble hormone binds, it dissociates the chaperone and allows the bound receptor to migrate to the nucleus and bind to DNA
• This leads to transcription of genes where the hormone is bound to.

Question 4

Effects of hormones on intracellular receptors are _____ and _______

Answer 4

slow; long-lasting

Question 5

A large fraction of theraputic drugs target a family of transmemebrane receptors known as _________

Answer 5

G-Protein Coupled Receptors; GPCRs

Question 6

At rest, the receptor is bound to a trimer of G-proteins called the ____, _______, and ______ proteins. The alpha G-protein is bound to ___ at rest. Binding of the ligand triggers change that causes ____ to be released and the alpha protein binds to __ , breaking the G-protein complex. To terminate the cycle, the alpha subunit will bind to ____ and hydrolyze it, releasing a phosphate and converting it back to _____. The system can assemble back again in its resting form.

Answer 6

• alpha, beta and gamma
• GDP
• GDP
• GTP
• GTP
• GDP

Question 7

________ proteins that can affect the rate of which GTP is hydrolyzed by the alpha subunit.

Answer 7

Regulators; RGS

Question 8

The beta gamma complex can ____ potassium channels and ____ cacium channels

Answer 8

activate; inhibit

Question 9

What enzyme does the beta gamma complex affect?

Answer 9

PI3 kinase

Question 10

What are 2 of the most common G-protein mediated signalling cascade?

Answer 10

• Adenylate Cyclase (AC)
• Phospholipase C (PLC)

Question 11

What is the effect of receptors coupled to Gs on AC enzyme?

Answer 11

Gs increases the activity of AC.

Question 12

What is the function of AC?

Answer 12

• increases the production of cAMP which activates cAMP dependent protein kinases
• therefore, an increase in AC causes the production of cAMP

Question 13

What effect does Gi have on AC?

Answer 13

Gi inhibitd the activity of AC leading to no-less production of cAMP and less activation of protein kinase

Question 14

What is the effect of Gq on PLC?

Answer 14

it increases the acitivty of PLC which leads to the production of inositol triphosphate (IP3) from the breakdown of PIP2.

Question 15

IP3 triggers the release of ____ from the ER, which can influence a variety of signalling pathways.

Answer 15

Intracellular Ca2+ stores

Question 16

What is the other byproduct of PIP2 breakdown which leads to the activation of protein kinase C and target substrates?

Answer 16

DAG, diacylglycerol

Question 17

What is CaM-E?

Answer 17

• Calmodulim; calcium binds to calmodulin which targets proteins and activates their activity.

Question 18

Protein Kinase C is a type of enzyme that will take ____ and use it as source of phosphate to transfer a phosphate to a substrate and change its activty.

Answer 18

ATP

Question 19

How are tyrosine kinase receptors different from G-protein coupled receptors?

Answer 19

Tyrosine kinase don’t rely on a second set of cascading, signaling molecules that are coupled to the receptor.

Question 20

Activation of TKRs is driven by _____ of receptors in the presence of a ligand, causing the receptors to ___ and become activated.

Answer 20

Dimerization; autophosphorylate

Question 21

Which type of receptor is membrane permeable?

Answer 21

Intracellular receptors; steroids

Question 22

Which receptor is circulating in form of drugs?

Answer 22

Intracellular receptor; bound to carrier globulin because of low solubility in plasma; also variable in cell surface receptors

Question 23

How do intracellular receptors and cell surface reeceptors different in terms of speed of response?

Answer 23

• Intracellular receptors are slow as it requires DNA binding and activation of target genes
• Cell surface receptors are fast as there is rapid transduction via protein conformational change and intracellular signalling cascades.

Question 24

What is the fastest mechanism of signaling in the body?

Answer 24

Ion channels

Question 25

Ion channels allow ions to cross the plasma membrane ____, leading to changes in ______ ________

Answer 25

Rapidly; membrane voltage

Question 26

A voltage-activated Na+ channel response (fast/slow) ____ to changes in membrane voltage. The channel sits in the _________ and have charged amino acids that are in the __________ electric field

Answer 26

rapidly; plasma membrane; transmembrane

Question 27

____________ channels open or close in response to binding of a small signaling molecule; they also play a major role in synapses in the CNS.

Answer 27

Ligand-gated channels.

Question 28

What is agonism?

Answer 28

• Refers to a substance/drug which binds to a receptor and influences its activty.
• usually depicted as a concentration-response curve.

Question 29

What is EC50?

Answer 29

• Effective concentration 50 refers to the concentration of the drug that yield in 50% of the maximal effect.

Question 30

What is Emax?

Answer 30

• refers to the maximal biological effect observed with the drug.

Question 31

What is efficay?

Answer 31

refers to the maximal response you can generate with the drug (emax)

Question 32

Concentrations can be plotted on a ____ scale of drug concentration or plotted on a ____ scale of drug concentration where they have a __ shape making it easier to see where the EC50 is.

Answer 32

linear; logarithmic; sigmodial

Question 33

What is potency?

Answer 33

• refers to the concentration dependence

Question 34

A drug with a strong potency has a ___ EC50

Answer 34

low

Question 35

A drug with a weak potency has a ____ EC50

Answer 35

high

Question 36

• A ___ agonist generate the maximal observed effect
• A ____ agonist can generate a fractional effective
• What cannot generte a biological effect on their own
• Which agonsits cause suppression of basal activity

Answer 36

• Full agonist
• partial agonist
• Antagonists
• inverse agonists

Question 37

• Full agonist causes all of the receptors or the maximum number of receptors to move to the __________ form
• Partial agonists will have some balance between the 2, favoring the ____ form
• An ____won’t have any intrinsic activity on it all; it won’t change
• Inverse agonists will cause the receptors to occupy their ____ form.

Answer 37

• activated
• activated
• antagonist
• inhibited