Lecture 1

Question 1

How do most drugs produce their effects?

Answer 1

They bind to protein molecules. Drug binding often leads to a conformational change in the protein.

Question 2

What are the four primary drug targets?

Answer 2

1. Ion channels.
2. Enzymes.
3. Carrier molecules.
4. Receptors.

Question 3

What is the exception to drug targets?

Answer 3

The important exception to protein at target sites is DNA on which a number of anti-tumour and anti-microbial drugs act directly on DNA (specific examples).

Question 4

Describe the effect of drugs on cell-cell communication?

Answer 4

To see the effect, you look at the effect on synaptic transmission (at the nervous level).

Question 5

How do you generate a response?

Answer 5

Action potential travels down the cell and releases the neurotransmitter stored in the vesicles at the pre-synaptic terminal. They then release the vesicles into the synapse, where the neurotransmitter is released. The neurotransmitter interacts with the spot-synaptic terminal.

Question 6

Describe a brief overview of the neurotransmission process?

Answer 6

1. Neurotransmitter synthesis.
2. Neurotransmitter release.
3. Action on receptors.
4. Inactivation.

N.B. Drugs can act on all of these processes.

Question 7

Describe a cholinergic nerve terminal?

Answer 7

The synapse of a nerve that releases ACh. Make ACh using choline as a precursor molecule. ChAT (enzyme) then synthesises it to ACh. Each is packaged into vesicles (transporters involved). When action potential (AP) comes down the axon, it activates voltage gated calcium channels. This allows calcium to flow in, flow of calcium into the terminal will lead the vesicles to fuse with the cell membrane. This will fill ACh into the synapse. It will then have effect on the post-synaptic cell by binding to different receptors. After ACh has bound to a receptor on the post-synaptic cell, it will be broken down into choline and acetate. Where the choline will be reused for another AP.

Question 8

Describe synthesis of acetylcholine?

Answer 8

Choline is taken up into the cell via a transporter and combined with AcCoA via an enzyme.

Question 9

Describe synthesis of acetylcholine?

Answer 9

AP comes down and activates voltage-dependent calcium channels. Calcium can flow into the terminal, then you have vesicular infusion and ACh released into the cleft.

Question 10

Describe ligand-gated channels?

Answer 10

Mediating fast transmission. Ion channel. So many biological processes are activated/inactivated by the flow of ions through cell membrane. Highly selective (doesn’t respond to other neurotransmitters). Select amongst the different ions (which ion they allow through).

Question 11

Describe Nicotinic ACh Receptor?

Answer 11

Stimulated by nicotine. Most of the actions are occurring through activation through this receptor. Series of subunits and different subunit composition (always 5 - each has 4 transmembrane domain). 2 ACh binding site (both need to be occupied for the receptor to be activated).

Question 12

What is the GABA(a) receptor commonly used for?

Answer 12

Anxiety, sedation and target for hallucinogenic mushrooms.

Question 13

What is glutamate receptor commonly used for?

Answer 13

A major source of study for ligand gated ion channels. But very few compounds make it onto the market as they have major adverse effects.

Question 14

What is nicotinic receptor commonly used for?

Answer 14

Main target for nicotine and nicotine replacement therapies.

Question 15

Describe GPCR?

Answer 15

All are monomeric protein (single subunit) that interact with G proteins. G proteins are essentially dimers (made up of alpha and beta and gimme subunit).

Question 16

What happens when the G protein is activated?

Answer 16

The alpha and beta separate and go on to produce an effect. The ligand binds to the receptor which will cause a conformational change in the receptor - leads to activation of the G protein and leads to downstream secondary messengers (cAMP).

Question 17

What classes do g proteins fall into?

Answer 17

Two classes:

1) The receptors that activate G-alpha-Q. This is M1, M3, and M5.
2) The receptors that activate G-alpha-i. This is M2 and M4 receptor.

Question 18

Describe M2 receptor in terms of neurotransmission?

Answer 18

Pre-synaptic receptor is M2 - pharmacologically distinct. Pre-synaptic function is different to post-synaptic receptor (these receptors are different). M2 is an inhibitory feedback loop. ACH is released from the nerve terminal where it acts post-synaptically to activate and excite post-synaptic cell. Activating it will decrease release of ACh and prevent further release.

Question 19

What happens if you block M2 receptor at the pre-synaptic terminal?

Answer 19

More neurotransmitter is released. Saturate the enzymes, and reach receptors it wouldn’t reach otherwise.

Question 20

Describe Tyrosine Kinase Receptors?

Answer 20

These are receptors that have built in enzymes. Mediating the factors of growth factors, cytokines and certain hormones. A conformational change activates the enzyme.