drug receptor interactions

Question 1

Selectivity

Answer 1

Binding to one receptor over another

Question 2

Specificity

Answer 2

Only binding to one receptor

Question 3

Therapeutic index

Answer 3

Dose that is lethal to 50%/dose that gives therapeutic effect in 50% of people
Want high TI

Question 4

Potency

Answer 4

Refers to conc causing particular response rather than max response i.e EC50

Question 5

EC50

Answer 5

Concentration that causes 50% of the maximal response

Question 6

Effect of competitive antagonist

Answer 6

Occupies receptors so more agonist needed for given response so shift logconc/response curve right

Examples: Atropine (for ACh) and Mepyramine (for His)

Question 7

Stereoisomers

Answer 7

Same formula and structure but with different 3D orientation

May have different affinity/efficacy so can act as antagonist

Question 8

Racemate

Answer 8

Mix of both stereoisomers
Curve is shifted to the right by the inactive isomer (if no affinity)

If isomer has some affinity se lower slope straight line

Question 9

Sidenafil citrate

Answer 9

Viagra

PDE5 inhibitor to inhibit cGMP-PDE to prolong cGMP lifetime for vasodilation

Question 10

Steroid receptor sequence

Answer 10

Steroid binds receptor in cytoplasm/nucleus (if oes)
This causes receptor to dissociate from chaperone and to bind to specific parts of DNA to increase or decrease transcription

Question 11

Structure of nuclear receptors

Answer 11

AF1 = N terminal
Zinc fingers = DNA binding domain
AF2 = Ligand binding domain

Question 12

Cys-loop type ionotropic receptors

Answer 12

Pentameric
nAChR
GABA
5-HT3

Question 13

Ionotropic glutamate type

Answer 13

Tetrameric

NMDA

Question 14

Calcium release ionotropic receptor

Answer 14

RyR
IP3R
Tetrametric

Question 15

nAChR structure

Answer 15

2alpha subunits, beta, delta, gamma
Linking of pore made by M2 helical segment
When ACh binds, alpha helices straighten and swing out to open the pore

Hill slope of 2

Question 16

Membrane bound guanylyl cyclase

Answer 16

Receptor is a dimer
Binds extracellular ligand ANP from atrial muscle
Activated receptor converts GTP to cGMP which activates protein kinase G
Causes vasodilation, salt excretion and phosphorylation to decrease Na+ reabsorption to lower BP

Question 17

Receptor ser/thr kinases

Answer 17

For heterodimers
Ligand binds type 2 receptor; this phosphorylates type 1 receptor to activate it
Recruits smad2/3 and phosphorylates
Smad can then oligomerise with co-smad
-> Smad-co-smad complex moves to nucleus and associates with DNA binding protein to target gene response element

Question 18

Receptor tyrosine kinases

Answer 18

Form homodimers
Have intracellular catalytic domain and extracellular regulatory domain

Type 1: EGFR; binding causes dimerisation of single chain

Type 2: insulin receptor; 2 chains already linked as dimer so binding just causes conformational change

Type 3: PDGFR (split kinase domain)

Question 19

Defects in TGFbeta pathway

Answer 19

TGFbeta mutations; colon cancer

Smad4 mutations; pancreatic cancer

Question 20

RTK signalling cascade

Answer 20

Binding causes dimerisation and mutual phosphorylation to activate intrinsic tyrosine kinase
Recruits adaptor proteins with SH2/3 domains
Signalling cascade to make Ras-GTP (activated by all RTKs); hydrolysis sped up by GAP
Can activate kinase cascade

Question 21

Receptors linked to soluble kinases

Answer 21

TMD dimerises upon agonist binding
Kinase domain associates with it (but encoded on separate gene)
Kinases phosphorylate themselves and receptors

E.g EPO (erythropoietin receptor); activates Jak-STAT signalling to release new RBCs

Question 22

GPCR structure

Answer 22

7 TMDs
3 intracellular (2 and 3 used for G protein binding)
Associated with heterotrimeric G protein; activation causes conformation change that leads to GDP loss and GTP binding

Question 23

ADP ribosylating enzymes that alter alpha subunit activity

Answer 23

Cholera toxin: blocks GTPase activity on Gs so it stays active and increases cAMP
Pertussus toxin: prevents activation of Gi so adenylyl stays active and increases cAMP

Question 24

Protein kinase A structure

Answer 24

2 regulatory domains that each bind 2 cAMP
Binding causes pseudo substrate part of regulatory domains to dissociate from catalytic subunits
These can phosphorylate CREB to alter gene expression

Question 25

Gq/11 coupled receptors

Answer 25

Stimulates PLCbeta to cleave PIP2 to DAG and IP3
DAG stays in membrane and activates PKC

IP3 binds receptors on ER to cause Ca2+ channel opening

Question 26

Phosphatidylinositol cycle

Answer 26

IP3 can be phosphorylated to IP4 (causes Ca2+ entry via PM)

OR dephosphorylated to IP2 to IP to inositol

Question 27

Lithium involvement in phosphatidylinositol cycle

Answer 27

Inhibits Inositol-1-phosphatase that converted IP to inositol
This blocks recycling of inositol to make new PIP2
used for bipolar disorder

Question 28

Mechanisms of GPCR desensitisation

Answer 28

1) Uncoupling receptor from G protein
2) Sequestration of receptors
3) Down-regulation of receptors e.g decreases receptor synthesis via effect of PKA on mRNA stability

Question 29

Homologous desensitisation to uncouple GPCRs

Answer 29

Only on agonist occupied GPCRs
G protein coupled receptor kinases GRKs phosphorylate Ser/Thr residues in cytoplasmic tails
-> Then GRKs (ARK1/GRK2 and B-ARK2/GRK3) dissociate and arrestins can bind C terminal
This blocks ability of G protein to interact with loop 3 binding point

Arrestin can then promote receptor internalisation (sequestration)

Question 30

Homologous desensitisation of Beta2 adrenoceptor

Answer 30

ARKs are B-ARK1 and B-ARK2

Phosphorylation of the C terminus increases affinity for Beta-arrestins that uncouple the receptor

Question 31

Heterologous sensitisation

Answer 31

Can happen on non-agonist occupied GPCRs

GPCR stimulation causes rise in 2nd messengers e.g cAMP for beta2-adrenoceptor

These activate kinases (e.g PKA) that phosphorylate C terminal tail and loop 3
This causes uncoupling of alpha subunit from GPCR to stop further stimulation
(can also cause switch of G protein e.g from s to i)

NB: PKA could phosphorylate other similar receptors doesn’t need agonist bound

Question 32

Agonist bias

Answer 32

Where an agonist specifically recruits one pathway and blocks another

Question 33

Arrestin3 involvement in morphine analgesia

Answer 33

In arrestin-3-KO mice, morphine causes increasing analgesia and less response side effects (response depression, constipation)

• Therefore we want to block this arrestin
• TRV130 receptor activation is a potent bias agonist that preferentially goes down G protein route to analgesia rather than arresting route to desensitisation and side effects

Question 34

Spare receptors

Answer 34

Receptors that don’t need to be occupied to get max response
There to sensitise the tissue so shift logconc/response curve left
These get occupied before we see a response of irreversible antagonism (e.g by BCM on mAChR)