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Medneuro- M2-2- NT systems > Pharmacology- Plested > Flashcards

Pharmacology- Plested Flashcards

1
Q

name the main receptor types

A
  1. ionotropic (ion channel and electrochemical gradient)
  2. metabotropic (G protein cascade activation)
  3. TyrK (phosphorylated)
  4. nucleotropic
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2
Q

a modulator…

a. binds and activates receptor
b. binds at a different site from agonist, does not activate it but changes the response of the drug-receptor complex
c. blocks receptor
d. increases transcription of receptor

A

b

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3
Q

what is ‘on-rate’ K-on?

A

the second order rate at which a drug binds to receptor. limited by diffusion to be ≤10^8. in order to get the forward rate–> multiply by concentration
–> the on-rate depends on the concentration of the drug

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4
Q

what is the ‘off-rate’ K-off?

A

the first order rate at which a drug unbinds from receptor. It is the inverse of the life time of the drug-receptor complex. the off rate is independent of concentration but it is dependent on the time the drug acts on the receptor;
- units 1/s

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5
Q

the difference between K-on and K-off is…

a. K-on is independent of concentration and K-off is dependent on concentration.
b. K-on is dependent on concentration and K-off is independent of concentration, but is depending on the time the drug acts on the receptor
c. both K-on and K-off are dependent on drug concentration, bur K-on is a measure of the drug affinity
d. K-off depends on number of available receptors and K-on depends on drug concentration

A

b

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6
Q

What is the dissociation constant - Kd?

A
  • the ratio between K-off/K-on –> (K-1)/(K+1) (in Molar)
    agonist Kd- Ka
    antagonist Kd- Kb
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7
Q

why is the dissociation constant Kd is K-off/K-on?

A

it is the ratio between K-off/K-on because if it were the other way around we would get units of 1/M which is hard to understand in terms of drug potency.

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8
Q

what is the Hill-Langmuir equation? (equation + meaning), where did it originate ?

A
  1. originally: y= (N/(k’ +kN)) -M –> which is a rectangular hyperbola;
    with: y= the response ; N= nicotine concentration ; M= threshold ; k and k’ are constants.
  2. the Hill Langmuir equation is an extreme case of the equation above–> It describes the fraction of the occupied receptors as depending on the concentration of the agonist [A] and Kd.
    Therefore:
    Par = Pr * ([A]^n/(Kd +[A]^n)) –> n is the Hill Slope; Par is the bound receptor and drug; Pr = free receptor
    –> the response Par is the response of the unbound receptor to the concentration of [A]
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9
Q

the Hill-Langmuir equation…

a. the Hill-slope n indicates the the number of binding sites
b. indicates the efficacy of the agonist
c. is purely empirical, and doesn’t tell us how receptor work
d. gives information about the binding affinity

A

c

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10
Q

describe the 3 state model

A

the 3 state model says that we much have at least 3 states of drug-receptor interaction:

  1. A + R- receptor is vacant, and agonist is unbound
  2. AR- agonist is bound to receptor –> formation of the drug receptor complex but it is inactive
  3. AR*- drug-receptor complex is active
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11
Q

competitive antagonism…(which answer is WRONG?)

a. a competitive antagonist binds at the same site as the agonist
b. low affinity antagonist unbinds quickly from receptor so agonist can bind
c. the potency of antagonist can be determined by the time it stays bound to receptor
d. only if the receptor is constitutively active in the absence of ligand the antagonist can work
e. it is hard to determine the difference between a weak partial agonist and a competitive antagonist

A

d

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12
Q

which of the following statements is true?

a. the affinity of a true competitive antagonist can be understood using the Schild method
b. the affinity of a true competitive antagonist can be better understood using the Hill equation or IC50

A

a

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13
Q

what is the Schild equation?

A

r = 1+ ([B]/Kb)
with: r= dose ratio; [B] antagonist concentration; Kb= inhibition constant, the concentration of B that inhibits the max. response by 50%

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14
Q

the Schild method…(which answer is WRONG?)

a. is independent of choice of agonist
b. enables us to obtain a microscopically correct binding constant Kb from any experiment
c. can be used to classify receptors in different tissues
d. is a null method
e. can be used to determine the quality of both competitive and non-competitive (irreversible) antagonist

A

e

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15
Q

what are the essential postulates of the Schild method?

A
  • equal response: receptor response only depends on the mean occupancy of the receptor by the agonist
  • exclusive bunding: the binding of a competitive antagonist and agonist are mutually exclusive
  • binding only: antagonist binding doesn’t alter the shape of the receptor
  • equal affinity: if there are multiple sites, then B has the same affinity at all sites
  • equilibrium: measurements are made at equilibrium
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16
Q

how can the exclusive binding be detected?

A

easily detected as insurmountable antagonist

17
Q

in the Schild method, if r=2, how would this affect the equation?

A

r = 1 + ([B]/Kb)
–> rearrange and log the equation:
log(r-1) = log([B]/Kb) –> log(r-1) = log[B]-log(Kb)
–> if r=2:
log(2-1) = log[B]-log(Kb) –> log(1) = 0 –>/ + log(Kb)

this special case gives us: log[B] = log(Kb)
–> this r=2 case is very important and can only exist when [B] = Kb

18
Q

Why can we get info about Kb (antagonist constant) but not about Ka (agonist)? what is the difference between the two?

A

The difference between an agonist and an antagonist is that agonist has two features- affinity and efficacy, whereas antagonist only has affinity, as it does NOT elicit a response. –> this is why we can get Kb but not Ka as we only know info about the affinity.

19
Q

Randomisation…

a. tells us about correlation AND causation
b. tells us about causation but NOT correlation
c. tells us about correlation but NOT causation
d. allows us to increase effect size

A

c

20
Q

Randomisation…(which statement are WRONG)

a. removes sources of bias including those that you don’t know about
b. is not ethical
c. can prove correlation but not causation

A

b, c

21
Q

what was the tea tasting experiment? what can it tell us about good scientific practice?

A
  • a lady claimed she can recognise tea cups where the tea was poured in before milk and vice versa
  • test: T= tea first ; M= milk first
  • sequence: TTMMTMT –> 70 different ways to make the sequence
  • chances of guessing the sequence are 1:70; with a 50/50 chance to guess each cup correctly
  • -> if the lady guesses correctly, this doesn’t make the results significant, because the chance of guessing correctly are so high!
  • -> in order to determine the power if the results–> one should repeat the experiment many times and randomise the trials
22
Q

what is the odds ratio (OR)? + example

A
  • the OR is the ration between chance of event for 2 groups
  • quantifies the strength of the association between two events, A and B–> the odds of A in the presence of B and the odds of A in the absence of B
  • Example: drinking beer and gender –> P(beer/male) and P(beer/female)
23
Q

how many receptor families bind glutamate? what are they?

A 
4 families: 
NMDA
AMPA
Kainate
Delta
24
Q

how many binding sites do glutamate receptors have?

A

4

25
Q

describe the process of glutamate binding and channel activation

A
  • the binding sites of Glu receptors have 2 lobes which are moving in a clamshell manner (ligand binding domain- LBD)
  • the domain closure is correlated with agonist efficacy:
  • -> unbound clamshell is open and inactive
  • -> when agonist binds the clamshell closes at different degrees: partially = weak/partial agonist; fully = full agonist
  • -> the more the clamshell closes the higher the efficacy of the drug
26
Q

what was the method used to discover the way glutamate binds to receptor? describe the procedure

A

method: molecular binding simulation
- looked into the clamshell and the position of glutamate when Glu was present
- -> when glutamate is there, the clamshell is in a low energy conformational state–> closing
- -> glutamate goes toward the receptor and interacts with arginine –> it gets passed from one position (side chains) to another until positioned correctly at the clamshell and it can close.
- -> this is called electrostatic funnelling

27
Q

what experiment was done to determine the importance of electrostatic funnelling?

A
  • mutant experiment, where binding paths were disrupted
  • result: disrupted binding paths slowed down both on and off rates
  • off pathway mutations have small and opposite effect–> glutamate entered the cleft upside-down and clamshell didn’t close

–> this mechanism is true to ALL GluRs

28
Q

why are inotropic glutamate receptors amongst the best understood receptors?

A

We have high-resolution crystal structures, and precise

measurements of activity from electrophysiology

29
Q

what 2 effects of Ach were discovered by Dale?

A
  • 1 ug of Ach caused vasodilation which could be blocked by atropine (BP decrease)
  • following atropine –> 5000 fold more Ach –> raise BP due to high ACh levels, could be blocked by nicotine.

–> this was the evidence that 2 different NT systems (receptor types) use ACh as their NT

30
Q

what are the 2 receptors that bind ACh?

A

nicotinic receptors - selectively activated by nicotine

muscarinic receptors - selectively activated by muscarine

31
Q

How can ACh bind to both nicotinic and muscarinic receptors, when nicotine and muscarine are so different from each other?

A

ACh is a flexible molecule that can adopt different conformations when binding to different receptors:

  • trans conformation - muscarine
  • Gauche conformation - nicotine
32
Q

Which of the following statements about nicotinic ACh receptors is/are correct?

a. the nAChR has an extracellular binding domain which is a glycine receptor
b. the nAChR is membrane ion channel composed of 2 subunits
c. ACh binds to the extracellular receptor and moves to the first subunit and from there to the 2nd subunit –> conformational change in the 2nd subunit)
d. ACh binds to arginine in the binding sites
e. arginine acts as a surrogate in empty spaces of recepptor to prevent nicotine from going the wrong way

A

a, b, c, e

33
Q

Which of the following statements about nicotinic ACh receptors is/are WRONG?

a. The muscle receptor is quite different from the ganglion and CNS types. It has a unique set of subunits.
b. The ganglion and CNS receptor types use similar subunits.
c. the selectivity of subunits is easily achieved
d. different combination of subunits can generate different responses to ligands and form different receptor types

A

c

34
Q 
muscarinic receptors (mAChR) are metabotropic receptors which are coupled to G proteins 
True or False?
A

true

35
Q

which of the following statements is/are correct?

a. mAChR are faster than nAChR
b. mAChR are slower than nAChR
c. the concentration of ACh needed for mACh receptor activation is much lower than nAChR so ACh stays bound for a long time despite decrease in ACh concentration
d. mAChR activate Na+ channel
e. activation of mACh is indirect

A

b, c, e

36
Q

why is it easier to make antagonist for ACh receptors than agonist?

A
  • antagonist don’t need to activate the receptor, bit only bind to it and block binding of an agonist
  • antagonists are symmetric, spanning and binding multiple binding sites which increases their affinity and block of an entire receptor
  • agonist molecules are VERY small because they need to change the conformation of the receptor and activate which involves very fine molecular process

Medneuro- M2-2- NT systems (11 decks)

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