Lecture 15- Receptor theory pt2

Question 1

affinity

Answer 1

does it bind (Kd)

Question 2

efficacy

Answer 2

does it evoke the correct response in the cell

Question 3

asthma is

Answer 3

reversible airflow obstruction and bronchospasm

Question 4

in astma allergen/ stimulus causes

Answer 4

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

Question 5

what sort of drug can be used to relax the airways

Answer 5

functional antagonist for B2 adrenoreceptors

Question 6

problem with B2 adrenoreceptors antagonist

Answer 6

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

Question 7

salbutamol 9drug of choice for asthma)

Answer 7

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

Question 8

what can increase selectivity for lung tissue

Answer 8

route of admin e.g. inhaler

Question 9

salmeterol (long acting)

Answer 9

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

Question 10

would ideally like to give salmeterol since it

Answer 10

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

Question 11

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

Answer 11

the smaller the response

Question 12

the more receptors a cell has

Answer 12

the larger the response the ligand will have

Question 13

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

Answer 13

redundant

Question 14

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

Answer 14

spare

Question 15

if less than 100% occupancy = 100% response

Answer 15

spare receptors

Question 16

example of spare receptors

Answer 16

above 10% of occupancy of mAChR gives maximal contraction

over 90% of receptors are spare

Question 17

wbhy do spare receptors exsit

Answer 17

due to amplification in the signal transduction pathway

Question 18

why have spare receptors

Answer 18

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

Question 19

receptor no. on cells is

Answer 19

not fixed

Question 20

receptor number tends to

Question 21

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

Answer 21

down regulation (number of receptors on tiossue reduce)

Question 23

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

Answer 23

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

Question 25

are all agonsits equal for the same receptor?

Answer 25

no

• different affintiies and different efficacies

Question 26

salbutamol has

Answer 26

different efficacies

Question 27

salmeterol

Answer 27

different affinities (much higher affinity for B2 than B1)

Question 28

what explains that different agonists are not equal at the same receptor

Answer 28

full and partial agonists

Question 29

full agonists

Answer 29

EC50 <kd></kd>

<p>- +- spare receptors</p>

<p>- endogenous ligands</p>

</kd>

Question 30

EC50 <kd></kd>

Answer 30

affinity is higher than potency

Question 31

partial agonists

Answer 31

EC50= kd

• no spare receptors
• all receptors occupied - insufficient intrinisc efficacy for maximal response

Question 32

maximal response indicates

Answer 32

intrinsic activity- full agonists

• usually endogenous

Question 33

reduced response indicates

Answer 33

lower intrinsic activity- partial agonist

Question 34

paertial agonism is dependnet on ligand type, but also

Answer 34

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)

Question 35

in full agonism increasing receptor number

Answer 35

will not increase response due to spare receptors

Question 36

in partial agonism, increasing the number of receptors

Answer 36

will icnrease the response

Question 37

relevance of partial aognsits as drugs

Answer 37

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

Question 38

heroine treatment with buprenorphine

Answer 38

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

Question 39

withdrawal of abstiencne syndrome

Answer 39

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

Question 40

antagonists block the ffect of agonist svia

Answer 40

1) Reversible competitive antagonism
2) Irreversible competitive antagonism
3) Non-competitive antagonism (generally allosteric- can event work post receptors)

Question 41

1) Reversible competitive antagonism

Answer 41

Relies on a dynamic equilibrium between ligands and receptors- binds to orthosteric site

Question 42

orthosteric site

Answer 42

active site equivalent

Question 43

with reversible compeitive antagonsim, the more antagonist added

Answer 43

the more inhibition

Question 44

reversible compeitive antagonists cause a parallel shift to the …… of the agonists conc-repsonse cruve

Answer 44

right

• if you added more agonist, then it would shift back to the left

Question 45

an example of compeitive antaognism in the clinic

Answer 45

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

Question 46

irreversible compeitive antago ism

Answer 46

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

Question 47

An example of irreversible competitive antagonism in the clinic

Answer 47

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

Question 48

Non-competitive antagonism

Answer 48

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

Question 49

non-competitive antagonist also known as

Answer 49

negative allosteric modulation

Question 50

example of allosteric compound for GOCRs

Answer 50

maraviroc

• Negative allosteric modulator (NAM) of chemokine receptor 5 (CCR5) Used by HIV to enter cells.
• Used in AIDS.