Lecture 15- Receptor theory pt2 Flashcards

(50 cards)

1
Q

affinity

A

does it bind (Kd)

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2
Q

efficacy

A

does it evoke the correct response in the cell

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3
Q

asthma is

A

reversible airflow obstruction and bronchospasm

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4
Q

in astma allergen/ stimulus causes

A

contraction of the smooth must of the airways- bronchospasm alphaS GPCR - adrenaline binds to B2 adrenoreceptors - increase in cAMP

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5
Q

what sort of drug can be used to relax the airways

A

functional antagonist for B2 adrenoreceptors

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6
Q

problem with B2 adrenoreceptors antagonist

A

there B-adrenoreceptors elsewhere e.g. the heart o Also increases force and rate of contraction - Need selective/specific activation of B2-adrenoreceptors in the airways

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7
Q

salbutamol 9drug of choice for asthma)

A
  • Has selective efficacy and affinity for B2 o Will also activate B1- problem for patients with angina (positive chronotropy)
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8
Q

what can increase selectivity for lung tissue

A

route of admin e.g. inhaler

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9
Q

salmeterol (long acting)

A

much higher affinity for B2 than B1 - no selective efficacy - selectivity based on affinity

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10
Q

would ideally like to give salmeterol since it

A

binds really well to b2 and not well to B1 (less side effects) however it is insoluble

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11
Q

the smaller the number of receptors for an agonist on a tissue

A

the smaller the response

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12
Q

the more receptors a cell has

A

the larger the response the ligand will have

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13
Q

when the maximum response has been evoke, increasing the number of receptors is

A

redundant

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14
Q

what are receptors called if they are not required to evoke a maximum response

A

spare

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15
Q

if less than 100% occupancy = 100% response

A

spare receptors

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16
Q

example of spare receptors

A

above 10% of occupancy of mAChR gives maximal contraction

over 90% of receptors are spare

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17
Q

wbhy do spare receptors exsit

A

due to amplification in the signal transduction pathway

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18
Q

why have spare receptors

A

Spare receptors increase sensitivity/ potency- allowing responses at low conc of agonist

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19
Q

receptor no. on cells is

A

not fixed

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20
Q

receptor number tends to

A
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21
Q

when receptors are used frequently i.e. haev higha citivty

A

down regulation (number of receptors on tiossue reduce)

23
Q

when receptors are in high use and the number of receptors becomes subsequently downgraded

A

the effect of morphine will become less affective the more it is used due to down regulation of receptors

25
are all agonsits equal for the same receptor?
no - different affintiies and different efficacies
26
salbutamol has
different efficacies
27
salmeterol
different affinities (much higher affinity for B2 than B1)
28
what explains that different agonists are not equal at the same receptor
full and partial agonists
29
full agonists
EC50

- +- spare receptors

- endogenous ligands

30
EC50
affinity is higher than potency
31
partial agonists
EC50= kd - no spare receptors - all receptors occupied - insufficient intrinisc efficacy for maximal response
32
maximal response indicates
intrinsic activity- full agonists - usually endogenous
33
reduced response indicates
lower intrinsic activity- partial agonist
34
paertial agonism is dependnet on ligand type, but also
receptor number In partial agonism, increasing the number of receptors will increase the response. In full agonism, increasing the number of receptors will not increase the response (due to spare receptors)
35
in full agonism increasing receptor number
will not increase response due to spare receptors
36
in partial agonism, increasing the number of receptors
will icnrease the response
37
relevance of partial aognsits as drugs
**à** Can allow a more controlled response à Can work in the absence or low levels of (endogenous) ligand… but can act as antagonist if high levels of full agonist
38
heroine treatment with buprenorphine
will inhibit the effect of heroin: * Partial agonist can provide antagonism * Outcompetes heroin (higher affinity), but won’t give such a big response **Heroin** is a full agonist at U-opioid receptor. Addiction related to physical and psychological dependence
39
withdrawal of abstiencne syndrome
Relevant to drugs of abuse and clinically used drugs. Generally opposite to acute drug effects- contributes to continued drug taking/ withdrawal eefct. à Sustained drug-taking leads to tolerance e.g. reduced receptor numbers and reduced post-receptor signalling). When the drug is withdrawn, the endogenous ligands are now less effective- hence withdrawal symptoms
40
antagonists block the ffect of agonist svia
## Footnote 1) Reversible competitive antagonism 2) Irreversible competitive antagonism 3) Non-competitive antagonism (generally allosteric- can event work post receptors)
41
**1) Reversible competitive antagonism**
Relies on a dynamic equilibrium between ligands and receptors- binds to **orthosteric site**
42
orthosteric site
active site equivalent
43
with reversible compeitive antagonsim, the more antagonist added
the more inhibition
44
reversible compeitive antagonists cause a parallel shift to the ...... of the agonists conc-repsonse cruve
right - if you added more agonist, then it would shift back to the left
45
an example of compeitive antaognism in the clinic
**Naloxone:** * High affinity, competitive antagonist at U-opioid receptors * High affinity means it will compete effectively with other opioids e.g. heroin Reversal of opioid-mediated respiratory depression
46
irreversible compeitive antago ism
Occurs when the antagonist dissociates slowly or not at all With increased [antagonist] or increased time more receptors are blocked by antagonist - Non- surmountable **Causes a parallel shift to the right** of the agonist-con-response curve and at higher conc suppress the maximal response
47
**An example of irreversible competitive antagonism in the clinic**
**Pheochromocytoma** **e.g. Phenoxybenzamine- non-selective irreversible** * A1 adrenoreceptor blocked used in hypertensive episodes of pheochromocytoma * Once bound phenoxybenzamine cannot be out-competed by high levels of adrenaline
48
**Non-competitive antagonism**
**Allosteric sites** (anywhere that’s not an orthosteric site) provides binding sites for: - Agonists (potential novel drug targets) - Molecules that enhance or reduce effects of agonist - No competition for binding site- reduce orthosteric ligand affinity or efficacy
49
non-competitive antagonist also known as
negative allosteric modulation
50
example of allosteric compound for GOCRs
maraviroc - Negative allosteric modulator (NAM) of chemokine receptor 5 (CCR5) Used by HIV to enter cells. - Used in AIDS.