Sites Of Drug Action

Question 1

Who was John Langley?

Answer 1

In 1905 Langley identified the idea of receptive substances by using an organ bath, adding different drugs and measuring a response.

He found that nicotine could be blocked by curare and similarly pilocarpine with atropine.

Question 2

What did Paul Erhlich Coin? And when?

Answer 2

In 1908 Erhlich coined the term receptors. Won a nobel prize.

Question 3

Compare an endogenous and exogenous agonist.

Answer 3

Endo comes from w in the body.

Question 4

What are 6 sites of drug action?

Answer 4

Transporters, Receptors (Ligand-gated channels, GPCR, Catalytic, Nuclear), Enzymes

Question 5

Compare an antiport and symport’s mechanism of action

Answer 5

Primary, uses ATP vs secondary, relies on electrochemical gradient

Question 6

What are 4 key drug actions at transporters? IPTR

Answer 6

IPTR

1. Inhib of CNS transporters can control neurotransmitter levels
2. Involved in absorption, distribution and elimination (pharmacodynamics) of drugs
3. can influence drug toxicity by controlling concentrations of drugs in a particular area
4. development of resistance. seen with some anticancer, antiviral, antibacterial and anticonvulsant drugs as they actively pump them out of the target cell

Question 7

What are ABC transporters?

Answer 7

ATP-binding cassette transporters use ATP hydrolysis to pump against a concentration gradient actively.

Question 8

Name 2 important ABC transporters?

Answer 8

P-glycoprotein (p-gp) and Cystic fibrosis transmembrane regulator (cftr)

Question 9

What are SLC transporters?

Answer 9

Solute-linked carrier

Secondary. Both solutes have higher concentrations on the same since of the cell. Pumps one out while pumping the other in at the same time.

Question 10

Name 3 important SLC transporters and what drug commonly targets them?

Answer 10

Antidepressants.
Monoamine transporters; DAT (dopamine), NET (noraadrenaline), SERT (serotonin)

Question 11

Compare the structure of Ligand-gated ion channels, G protein-coupled receptors, Catalytic receptors and Nuclear receptors.

Answer 11

L-G
- transmembrane domains: 4
- N terminus: outside cell
- C terminus: outside cell
- has intracellular area
- 4-5 monomers are required to be active.

GPCR
- transmembrane domains: 7
- N terminus: outside cell
- C terminus: inside cell
- G protein coupling domain inside cell
- 1 monomer are required to be active.

Catalytic
- transmembrane domains: 1
- N terminus: outside cell
- C terminus: inside cell
- 2 monomers are required to be active. (must be dimerised and autophosphorylated)

Nuclear
- transmembrane domains: 0
- N terminus
- C terminus: binding domain
- DNA domain: zinc fingers

Question 12

Describe the mechanism of action of Ligand-gated ion channels and name 6 ligands that bind here.

Answer 12

the ligand binds, conformational change, ions flow in, change in membrane potential, cellular response.

Ach
ATP
Glycine
GABA
Glutamine
5-HT

Question 13

What is the Nicotinic Acetylcholine (ACh) receptor?

Answer 13

A type of ligand-gated ion receptor. Has 5 subunits. 2 Ach molecules bind causing it to open and allow cation to pass through (Na+, K+, Ca2+ sometimes)

Question 14

What % of the genome are G-protein-coupled receptors? How many have been matched (name some)?

Answer 14

3%
Muscarinic w/ Glucagon
Adenosine w/ Histamine
Canaboid w/ PTH
Dopamine w/ seratonin

Question 15

How do catalytic receptors become functional?

Answer 15

Two monomers dimerize when a ligand is bound, and undergo autophosphorylation.

Question 16

what are the 5 main types of catalytic receptors and provide some functions?

Answer 16

Receptor Tyrosine Kinases - e.g. insulin
Receptor Serine / Threonine Receptors
Cytokine Receptors - Associate w/ proteins that have tyrosine kinase activity
Receptor Guanylyl Cyclases - intrinsic cyclase activity e.g. ANP
Receptor Protein Tyrosine Phosphates - e.g. a tumour suppressor

Question 17

What are EGFs and how do they trigger a signalling cascade?

Answer 17

• Epidermal Growth Factor receptor
• when activated during autophosphorylation leads to the recruitment of adaptor signalling molecules which relay signal.

Question 18

What proteins are present in a nuclear receptors active and inactive forms?

Answer 18

Inactive
- co-repressor / inhibitory proteins

Active
- agonist binding causes a conformational change
- co-repressor dissacosiates
- co-activator recruited
- gene transcribed

Question 19

Compare class 1 and class 2 nuclear receptors.

Answer 19

Draw Venn diagram comparing:
- hetero/ homo
- steroid/ lipid ligands
- high/ low affinity
- synthesised as inactive w HSP in the cytoplasm/ bound to co-repressors
- ligand binding induces HSP dissociation/ induces co-repressor dissociation, co-activator binds

Question 20

What is the time scale for the 4 types of receptors? Why is this important?

Answer 20

Ligand-gates = milliseconds
G-protein = seconds
kinase-liked = hours
nuclear = hours

i.e. Asthma, would need something fast acting for bronchospasm