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PHRM824 > Exam 2 General Info > Flashcards

Exam 2 General Info Flashcards

1
Q

GABA-A orthosteric modulator

A

GABA

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2
Q

NMDA receptor orthosteric modulator

A

Glutamate / Glycine Site

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3
Q

GPCR orthosteric site

A

Can bind to many other drugs such a Z-hypnotics and other drugs on the sides. red and blue pieces passed around in class, compressed when an agonist binds, decompressed when unbound

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4
Q

GPCR terminuses

A

N outside of cell, C inside of cell

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5
Q

GPCR binding site?

A

In the transmembrane space close to the middle of the molecule

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6
Q

What is the G-protien complex made up of?

A

Alpha and Beta subunits & gamma

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7
Q

Nobel prize winners in 2012 for G-protein coupled receptors (possible EC)

A

Robert J. Lefkowitz and Brian K. Kobilka

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8
Q

Who discovered cyclic-amp and when? (This 100% EC he literally said in class)

A

Earl Wilbur Sutherland in 1971

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9
Q

What % of pharmaceutical drugs target GPCR

A

40%

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10
Q

How many classes of GPCR are there?

A

3 classes. A, B and C

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11
Q

Class A GPCR othersteric site is where? and where is the allosteric site?

A

Allosteric site is on the outside, orthosteric site is inside the receptor

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12
Q

Class B GPCR orthosteric site is where? and where is the allosteric site?

A

Allosteric is on the inside, orthosteric is on the top of the receptor

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13
Q

Class C GPCR orthosteric site is where? and where is the allosteric site?

A

“Venus fly trap” orthosteric site on top of the receptor, allosteric site inside the receptor like class A

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14
Q

Drug therapy in GPCR and where they try to bind?

A

Trying to find drugs that bind to allosteric sites of B and C because of the very similar structure and its hard to match “venus fly trap” orthosteric site.

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15
Q

Effectors of GPCRs

A

3 effectors, channels, enzymes and regulatory enzymes

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16
Q

Summary of G-proteins

A

receptor binds -> activates G-protein -> activated G-alpha or G-beta change the activity of an effector (usually an enzyme or an ion channel -> also changes the concentration which activates secondary messengers

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17
Q

Outcome of the G protein cycle

A

Alpha subunit starts off with a GDP but replaces it with a GTP when ligand binds to the receptor, and says fuck beta and runs away with GTP, cycle restarts when new alpha comes with GDP again

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18
Q

G-A-s (stimulatory) has 3 isoforms, what are they and what do they do?

A

g-alpha-s, g-alpha-s-XL (big bitch), g-alpha-olf (golf) they all stimulate adenylyl cyclases

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19
Q

G-A-I (inhibitory) what does it do?

A

inhibits adenylyl cyclases (has 7 isoforms) if we have to know them we should just die

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20
Q

G-A-q/11 ???? (who comes up with this stuff) wuts it do

A

it activates phospholipase C

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21
Q

G-A-12/13

A

recuit RHO guanine exchange factors (these help woth cell growth and cell shape

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22
Q

G-B-Y

A

5 beta and 12 gamma

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23
Q

what does adenylyl cyclase do?

A

converts ATP to cAMP dr watts loves these things + earl sutherland 👀👀👀👀 1971

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24
Q

how does cAMP exert its effects

A

through stimulating cAMP depended protein kinases (PKA)

25
Q

where do irreversible antagonists bind? (allosteric site or orthosteric site?)

A

orthosteric site, this means the agonist will not be able to bind

26
Q

what receptor subtype is likely to be involved with extremely fast drug response?

A

ion channels

27
Q

what receptor subtype is likely to be involved with extremely slow drug response?

A

steriod receptors

28
Q

how can we measure cAMP?

A

radioactive assays, protein-based biosensors-EPAC, fluorescent approach-HTRF

29
Q

phospholipase C gets activated by G-q and what happens? (secondary messangers)

A

it produces phosphoinositides and diacylglycerol

30
Q

cGMPs effector is what?

A

Guanyl cyclase

31
Q

what does cGMP activate?

A

PKG (protein kinase G)

32
Q

what is cGMP regulated by?

A

NO / NITRIC OXIDE

33
Q

is cGMP specific?

A

yes, much more specific than other messenger proteins

34
Q

What does viagra inhibit? (possible EC)

A

inhibits the breakdown of cGMP by phosphodiesterase 5 (PDE5)

35
Q

what do kinases do?

A

add a phosphate (can increase or decrease activity)

36
Q

what do phosphates do?

A

get rid of a phosphate (can increase or decrease activity)

37
Q

After receptor activation there is a homologous desensitization (rapid desensitization) done by what?

A

GRK (G-protein receptor kinases)

38
Q

What were GRK called initially? (possible EC)

A

B-ARK (woof)

39
Q

After desensitization arrestin comes into the drug and decides 2 things, what are they?

A

Recycles the drug (dephosphoralation) or it degrades it (lysosomal degradation, TRASHED)

40
Q

heterologous desensitization acts on multiple enzymes its non-agonist/receptor specific what can activate this?

A

PKA or PKC

41
Q

what are the 3 functions of arrestin?

A

signaling, desensitization and endocytosis

42
Q

what is agonist trafficking, biased agonism, ligand bias and differential engagement also called? (possible EC)

A

Functional selectivity

43
Q

What does functional selectivity require?

A

For the receptor to couple to multiple signal transduction pathways

44
Q

functional selectivity vs receptor selectivity

A

receptor selectivity is when the drug prefers a specific receptor while functional selectivity is once the drug has bound to the receptor it prefers a specific signaling pathway

45
Q

whats eli lilly’s “blockbuster drug” which is functionally selective? (possible EC)

A

Tirzepatide

46
Q

How functional selectivity can be used to design better drugs?

A

To induce one pathway such as B-arrestin when giving opioids to not get the bad side effects but keep the therapy. (ties in with HW2 about covid and Gq pathway and b-arrestin pathway

47
Q

functional selectivity and opioids

A

b-arrestin causes GI issues and tolerance issues when activated by opioids, you want to induce that pathway and favor G protein pathway to get analgesia (try to create ligands that a selective to G-protein pathways)

48
Q

Dr. Watts is currently studying functional selectivity with opioid receptors, which molecule is he targeting? (possible EC)

A

AC1 inhibitor adeylyl cyclase 1 (bypassing receptor and looking at specific pathways) (expressed primarily in the brain)

49
Q

How do signaling mechanisms work?

A

transduce extracellular signals (drug) into extracellular messages (effect)

50
Q

slowest types of receptors include these along with steroids

A

corticosteriods, mineralocorticoids, sex steriods, vitamin D and thyroid hormone

51
Q

How do intercellular receptors work?

A

once bound it goes to the nucleus where it stimulates the transcription of gene by binding to specific DNA sequences

52
Q

which of the 5 receptors can regulate gene transcription?

A

All of them, but they do them in different ways and different pathways

53
Q

Protein tyrosine kinase pathway?

A

unliganded receptors with inactive tyrosine kinases get dimerized by EGF which phosphorylates the tyrosine kinase in the cell. 2 Grb2 proteins connect to the tyrosines and when Grb2 is near the cell surface it activated the Ras pathway which leads to transcription factors. Ras also has a lipid attachment keeping it on the cell membrane.

54
Q

When the hormone binds to the extracellular receptor in protein tyrosine kinases when happens?

A

It goes through conformational change

55
Q

How does protein tyrosine kinases turn off?

A

Usually, turn off themselves by down regulations, but upon ligand binding, another safety switch is endocytosis of the receptor.

56
Q

what are some ligand-regulated transmembrane enzymes?

A

insulin, epidermal growth factors (ECF), and platlete derived growth factors (PDGF)

57
Q

cytokine receptors and their pathway

A

cytokine binds and it causes kinases to come and attach to the intercellular part of the receptor. Once it becomes dimerized it then becomes phosphorated through the JAK molecules (tyrosine kinases molecules) the phosphorylated molecules then recruit stat which is dimerized to be able to express gene regulation.

58
Q

cytokine storm is related to what?

A

Covid-19

59
Q

what are the 5 types of receptors talked about in class?

A

intercellular receptor, extracellular, Phosphorylated (tyrosine & cytosines) ion channels and GPCRs

PHRM824 (4 decks)

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