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PMCOL 200 > How Drugs Bind to Targets > Flashcards

How Drugs Bind to Targets Flashcards

1
Q

drugs that target intracellular receptors must be… (2)

A

able to cross pmemb. (lipid-soluble or have a transport mechanism)

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2
Q

ex of drugs w/ intracellular receptors

A

steroid hormones

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3
Q

LBD

A

ligand-binding domain

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4
Q

HSP

A

heat-shock protein

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5
Q

4 steps for drugs binding to intracellular receptor

A
  1. drug binds to LBD
  2. HSP or other chaperone is displaced
  3. drug/receptor complex translocates to nucleus and binds to response element
  4. DNA recognition domain is exposed, target genes are transcribed
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6
Q

effects of drugs that bind to intracellular receptors have ____-onset and ____-lasting effects

A

slow and long (not rapidly reversible)

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7
Q

GPCRs stands for…

A

G-protein coupled receptors

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8
Q

GPCR general cascade

A

extracellular ligand binding triggers conf. change in receptor which is coupled to intracellular G-protein cascade (separate from receptor)

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9
Q

GTP activity of G-protein (4)

A

receptor activation promotes GDP to GTP exchange of G-protein, Ga and Gby subunits dissociate, GTP hydrolysis by Ga acts as timer for signal termination, G-proteins reassemble

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10
Q

G-proteins are (homo/hetero)(di/tri/tetrameric)

A

heterotrimeric

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11
Q

which g subunit has GTPase activity?

A

G alpha

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12
Q

G beta and gamma subunits can…

A

influence activity of proteins (stay associated with pmemb.)

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13
Q

GPCRs are categorized by…

A

G alpha subtype

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14
Q

Ga 3 subtypes and targets

A
  1. Gs: activates adenylyl cyclase
  2. Gi: inhibits adenylyl cyclase
  3. Gq: phospholipase C
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15
Q

AC stands for…

A

adenylyl cyclase

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16
Q

PLC stands for…

A

phospholipase C

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17
Q

distinction between Gby and Ga subunit effects

A

Gby directly affects effector; Ga has affects on initial components that have downstream effects

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18
Q

G alpha s (AC) cascade (4)

A

agonist binds to rec, GTP-G(as) activates AC, enzymatic activity converts ATP to cAMP, cAMP activates PKA

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19
Q

PKA

A

protein kinase A

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20
Q

cAMP binding to PKA cascade (3)

A

cAMP binds to 2 R (reg) subunits of PKA, 2 C (cat) subunits dissociate, cat subunits phosphorylate substrates w/ ATP

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21
Q

G alpha i general cascade

A

suppresses AC, cAMP production and PKA activity

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22
Q

GPCRs vs intracellular (steroid) receptor distinction

A

GPCRs act very quickly

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23
Q

G alpha q (PLC) cascade (3)

A

agonist binds to rec, GTP-G(aq) activates PLC, enzymatic activity hydrolyzes PIP2 to IP3 and DAG

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24
Q

IP3 cascade (2)

A

binds to IP3 receptors in ER, Ca is released (can bind to calmodulin)

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25
Q

DAG cascade (2)

A

activates PKC which phosphorylates substrate w/ ATP

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26
Q

PKC stands for…

A

protein kinase C

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27
Q

TKRs stands for…

A

tyrosine kinase receptors

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28
Q

TKRs general cascade (4)

A

extracellular ligand binds to TKR causing dimerization, activation by autophosphorylation, phosphorylation of substrates w/ ATP

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29
Q

TKR ligand ex

A

EGF

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30
Q

TKRs vs GPCRs distinction

A

TKR is a receptor and a kinase that has effects on substrates (smaller cascade vs GPCRs)

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31
Q

Intracellular receptors (IR) vs cell surface receptors (CSR): memb. permeable drugs?

A

IR: yes
CSR: not necessary

32
Q

distinction between steroid hormone receptors vs GPCRs and TKRs

A

GPCRs and TKRs are cell surface receptors whereas steroid hormone receptors are intracellular

33
Q

Intracellular receptors (IR) vs cell surface receptors (CSR): circulating form of drug?

A

IR: bound to carrier globulin bcse low solubility in plasm (aq)
CSR: variable

34
Q

Intracellular receptors (IR) vs cell surface receptors (CSR): speed of response?

A

IR: slow (DNA binding)
CSR: fast (conf. change)

35
Q

Intracellular receptors (IR) vs cell surface receptors (CSR): response termination speed?

A

IR: slow (hydrophobic hormone usually bound to protein and gene expression is slow to reverse)
CSR: fast (rapid GTPase cycle)

36
Q

what is the fastest mechanism of signalling?

A

ion channels/elec. signalling (change in Vmemb.)

37
Q

2 types of ion channels

A
  1. ligand-gated

2. voltage-gated

38
Q

voltage-gated ion channel response of charged aa

A

change in V causes charged aa to move into transmembrane area

39
Q

agonism

A

substance/drug binds to a receptor and influences its activity

40
Q

curve that depicts drug activity

A

concentration-response curve

41
Q

EC50 stands for…

A

effective concentration 50

42
Q

EC50 is the…

A

[drug] to yield 50% max. effect

43
Q

Emax

A

max. biological effect of a drug

44
Q

E equation

A 
E = Emax. / 1 + (EC50 / [drug])  OR 
E = (Emax. x [drug]) / ([drug] + EC50)
45
Q

efficacy and relationship w/ Emax.

A

max. drug response; linear relationship w/ Emax.

46
Q

potency and relationship w/ EC50

A

concentration dependence; inverse relationship w/ EC50

47
Q

agonists are usually categorized based on their…

A

efficacy (size of response, height of graph)

48
Q

antagonist bind to receptor and generate…

A

no response on their own

49
Q

inverse agonists bind to receptor and…

A

suppress basal activity, if present (can be negative)

50
Q

full agonists bind to receptor and generate…

A

maximal response (Emax.)

51
Q

partial agonists bind to receptor and generate…

A

a fractional response (partial Emax.)

52
Q

antagonism

A

substance/drugs that binds to a receptor and influences its response to an agonist

53
Q

competitive antagonist

A

a compound that occupies the same binding site as agonist but does not elicit a response

54
Q

non-competitive antagonist effect of potency/efficacy

A

reduce agonists efficacy but not potency (decr Emax., same EC50)

55
Q

competitive antagonist effect on potency/efficacy

A

requires a higher conc. of agonist to generate a given response, potency but not efficacy is altered (same Emax., incr EC50)

56
Q

surmountable antagonist

A

high enough conc. of agonist displaces antagonist to achieve same Emax.

57
Q

Schild plot

A

measures dose ratio vs conc. of antagonist

58
Q

dose/conc. ratio

A

ratio of agonist EC50 w/ and wo/ an antagonist

59
Q

dose ratio equation

A

EC50 w/ antagonist / EC50 control

60
Q

x-intercept (pA2/pKi) of Schild plots reflect…

A

antagonist potency (small [antagonist] to double EC50 of agonist = strongly potent antagonist)

61
Q

how are Schild plots linear?

A

use log scales

62
Q

popular competitive antagonist for opioid receptors ex

A

naloxone

63
Q

t/f: partial agonists cannot act as antagonists

A

false, compete w/ agonist and decr response

64
Q

irreversible competitive antagonism

A

antagonist binds irreversibly to drug binding site and are not surmountable by agonist (might be referred to as noncompetitive antagonism)

65
Q

pure noncompetitive antagonism is…

A

binding of antagonist to allosteric site preventing activation of agonist bound receptor

66
Q

t/f: noncompetitive antagonists are surmountable

A

false

67
Q

allosteric potentiators

A

drugs/compounds that bind to an allosteric site and enhance agonist effect to receptor binding

68
Q

allosteric potentiators effect

A

incr efficacy, potency or both of agonist

69
Q

action of benzodiazepines

A

allosteric potentiators for GABA receptors (ligand-gated Cl channels) to alleviate symptoms of hyperexcitability from alcohol withdrawal

70
Q

allosteric potentiators effect on concentration-response curve

A

shift to left (same [GABA] = incr response)

71
Q

do [drug] vs drug bound and drug effect have the same relationship? why?

A

not always; amplification of response (more receptors present than needed for Emax.)

72
Q

Kd

A

dissociation constant; [drug] where 50% is bound to receptors

73
Q

B equation

A

B = (Bmax x [drug]) / ([drug] + Kd)

74
Q

ex of distinction btwn [drug] needed for Emax. vs all receptors bound

A

activation of a single GPCRs can generate many cAMP molecules and activate many PKAs (amplification)

75
Q

receptor reserve phenomenon

A

adding small amounts of irreversible competitive/noncompetitive antagonist still generates Emax. with incr [agonist] due to excess receptors (decr EC50/potency) until [antagonist] overcomes min. number of receptors needed to achieve Emax. w/ incr agonist

76
Q

What is B?

A

Receptor-bound drug

PMCOL 200 (27 decks)

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