L8 Receptor and other Drug targets

Question 1

Most drugs produce their effects by binding to protein targets (4)

Answer 1

-receptors
– ion channels
– enzymes
– transporters or carrier molecules

Question 2

Receptors sub-divided into 4 major types

Answer 2

1. ion channel receptors
2. G protein-coupled receptors
3. enzyme-linked receptors
4. nuclear receptors

Question 3

How are superfamilies distiguished

Answer 3

Based on how they transduce a signal
NOT by which stimulates them or the nature of the change in cell function

Question 4

Receptors within a particular superfamily use similar___ processes and so tend to have similar general ___

Answer 4

transduction
transduction

Question 5

Ion channel receptors

Answer 5

• Located in the cell membrane
• Collection of proteins form central pore / channel
• No agonist, ion channel closed, no ion flow
  (nicotinic acetylcholine receptor)
• 4 subunit proteins
• Ions cannot cross the cell membrane
• ACh binding alters ion channel structure and ions flow into the cell

Question 6

Ion channel receptors (ACh)

Answer 6

ACh binding alters ion channel structure and ions flow into the cell (nicotinic acetylcholine receptor)-NT agonist

Question 7

Ion channel receptor list

Answer 7

Location: Cell Membrane
Effector: Channels
Respond to: Fast NT
Time scale of action: Milisecond, very fast
Example: Nicotinic acetylcholine receptor

Question 8

G protein-coupled receptors

Answer 8

Drug attach to GPCR to cause a change in cell function of the g-protein
- has alpha, beta, gamma, GDP
- binds on membrane or extracellularly
- largest superfam of receptors

Question 9

G protein-coupled receptors list

Answer 9

Location: Cell membrane (7 transmembrane domains)
Effector: Enzyme of channel
Respond to: Hormones, slow NT
TimeSOA: Seconds, fast
Examples: Adrenoceptors and muscarinic acetylcholine receptors

Question 10

Effector of GPCR

Answer 10

An agonist binds to receptor to activate g-protein and activates the enzyme/channel

Question 11

g-protein example asthma

Answer 11

Salbutamol, a b2-adrenoceptor agonist relieves bronchospasm in asthma

Question 12

G proteins info

Answer 12

– intracellular effector systems or 2nd messenger cascades
– guanosine nucleotide binding proteins, GTP and GDP
– comprise 3 subunits (a, b, g)

Question 13

Main classes of G-alpha proteins

Answer 13

1. Ga(s) activates adenylate cyclase
2. Ga(i) inhibits adenylate cyclase
3. Ga(q) activates phospholipase C

Question 14

G proteins that link GPCRs to effector proteins to generate intracellular second messengers

Answer 14

– (Gas) adenylate cyclase generates cAMP
– (Gaq) phospholipase C generates inositol trisphosphate and diacylglycerol

Question 15

GPCR activation: airway smooth muscle

Answer 15

Salbutamol (agon) →
ß2-adrenoceptor →
G(s) (stimulatory GP) →
Adenylate cyclase (transducer/effector protein) →
cyclic amp →
relaxation (effect)

Question 16

Enzyme-linked receptors list

Answer 16

Location: Cell membrane
Effector: Enzyme
Respond to: Metabolism, growth, differentiation
TimeSOA: Minutes, slow
Examples: insulin receptor, receptors for cytokines, growth factors

Question 17

Enzyme linked receptor example insulin receptor

Answer 17

In diabetes, insulin is used to activate the insulin receptor, reducing blood glucose levels

Question 18

insulin receptor

Answer 18

tyrosine kinase → intracellular proteins → stimulate pathway for glucose transport (GLUT4) → translocate

Question 19

Nuclear Receptors list

Answer 19

Location: Intracellular
Effector: Gene transcription
Respond to: Steroid hormones and other
TimeSOA: Hours, very slow
Examples: Glucocorticoid, other steroid hormones

Question 20

Glucocorticoid drugs such as prednisolone are effective what agents

Answer 20

Anti-inflammatory

Question 21

How do drugs reach a nuclear receptor

Answer 21

cross the lipid membrane and bind to it. Receptor stimulation primarily results in altered gene transcription

Question 22

Nuclear receptors found

Answer 22

inside the cell in either the cytoplasm (Type I) or the nucleus (Type II)

Question 23

Glucocorticoid receptors are what

Answer 23

type 1 nuclear receptor

Question 24

Glucocorticoid Receptor agonist

Answer 24

Cortisol is one of the most a common pharmaceutical targets as a endogenous GR agonist.

Question 25

Protein targets for drug action (4)

Answer 25

Receptors
Ion channels - open for influx or out of ions
Enzymes
Transporters

Question 26

Agonist and receptors

Answer 26

Agonists bind to and activate receptors and cause transduction

Question 27

Antagonist and receptors

Answer 27

Will bind but not activate them, rather they prevent an endogenous molecule from binding.

Question 28

Blocker in ion channels

Answer 28

Blockers physically plug the ion channel. E.g – nifedipine is a Ca2+ channel blocker used to treat hypertension

Question 29

Modulators in ion channels

Answer 29

Modulators bind to accessory sites and modulate channel activity.
E.g-benzodiazepines enhance GABA-activated Cl- channel opening, used to treat anxiety

Question 30

Acetylcholine Receptors

Answer 30

There are two families of acetylcholine receptors; muscarinic and nicotinic.
Both families are found pre-synaptically (neurons that send neurotransmitter signals) as well as post-synpatically (neurons that receive neurotransmitter signals).

Question 31

Enzyme-Linked Receptors effector

Answer 31

protein kinase

Question 32

In Enzyme-Linked Receptors what do subsrate analogues do

Answer 32

They competitively inhibit the enzyme . E.g - analgesics like paracetamol inhibit cyclooxygenase(block fever and pain)

Question 33

False substrate in enzymes

Answer 33

Some drugs act as false substrates for enzymes. E.g – anti-cancer drug fluorouracil replaces uracil in purine biosynthesis, blocking DNA synthesis

Question 34

What is produced when there is a false substrate for enzyme

Answer 34

An abnormal metabolite

Question 35

Prodrugs and enzymes linked

Answer 35

Prodrugs need to be enzymatically converted to become active. E.g – ciclesonide is converted to the active metabolite in the lung, resulting in fewer adverse effects in non-airways

Question 36

Specific carrier proteins transport what and where

Answer 36

Specific carrier proteins transport ions and small organic molecules across cell membranes. E.g – glucose, amino acids, neurotransmitters, Na+, Ca2+ etc.

Question 37

Can some drugs inhibit transporters

fluoxetine

Answer 37

Yes - they will bind to the transporter to block the molecule of interest. E.g – anti-depressant drug fluoxetine inhibits the re-uptake of the neurotransmitter serotonin into neurones

Question 38

False substrates and transporters

Answer 38

– CNS stimulant amphetamine uses the noradrenaline transporter to enter nerve terminals and replace/release the neurotransmitters noradrenaline and serotonin

Question 39

False substrates and transporters accumulation

Answer 39

abnormal compound gets to accumulate

Question 40

Ga(s) protein

Answer 40

activates adenylate cyclase
adenylate cyclase generates cAMP

Question 41

Ga(i) protein

Answer 41

inhibits adenylate cyclase

Question 42

Ga(q) protein

Answer 42

activates phospholipase C
– phospholipase C generates inositol trisphosphate and diacylglycerol