Medicines delivered to the lungs

Question 1

What were the natural starting point for drugs such as salbutamol, dobutamine and xamoterol?

Answer 1

Natural neurotransmitters such as noradrenaline and adrenaline

Question 2

What are adrenergic receptors?

Answer 2

G protein receptors

Question 3

Where does the serine residue interact with in a catecholamine?

Answer 3

Phenolic group via hydrogen bonding

Question 4

Where does the aromatic ring of the Phe-290 (phenylalanine) react?

Answer 4

Catechol ring via van der waal interactions

Question 5

Where does the aspartic residue act on the catecholamine?

Answer 5

Protonated nitrogen by ionic bonding

Question 6

Define what a catecholamine is?

Answer 6

Any class of aromatic amines that include a number of neurotransmitters such as noradrenaline and dopamine

Question 7

Explain what the activation of beta 2 receptor agonists resulted in?

Answer 7

1. Bronchial relaxation in the lungs where there are many beta 2 receptors
2. Dilation of the airways

Question 8

Explain the action of adrenaline on the airways and why it was replaced with isoprenaline?

Answer 8

1. Adrenaline is only short acting and isn’t selective on Beta 2 receptors
2. It activated many different beta receptors which led to many side effects and cardiovascular effects
3. Isoetherine is more selective on the beta 2 receptors so is used as an anti-asthmatic

Question 9

Explain how isoprenaline was more selective to beta receptors compared to alpha receptors and how they made compounds more selective in the future?

Answer 9

1. Large bulky N alkyl substituent
2. No selectivity differences between different types of Beta receptors
3. Introducing alkyl substituents to the side chain made the compounds more selective to beta receptors

Question 10

In order to prevent COMT from turning molecules into inactive ethers, what was done about the molecules? What was the end result?

Answer 10

1. Meta-phenol group was replaced with a group that could selectively bind to the receptor, but couldn’t be metabolised
2. Production of Salbutamol by changing the meta-phenol group to a hydroxyethyl group

Question 11

What is chiral switching?

Answer 11

1. When a patented racemic drug is reaching the end of its patent
2. Companies then form the pure enantiomer that is proven to work better than the racemic form
3. Example: Salbutamol (R) is 68 more times active then (S) form

Question 12

Describe N-alkylation in terms of salbutamol?

Answer 12

1. Salbutamol has a bulky N-t-butyl group (NH- C- (CH3)3)
2. The bulkier the N- alkyl substituent meant loss of potency at alpha receptor (increased potency at beta receptor)
3. Bulky arylalkyl group can fit into a Beta adrenoceptor with a “hydrophobic pocket”

Question 13

What is salmefamol compared to salbutamol?

Answer 13

Has a Bulky N-arylalkyl is 1.5 times more potent than salbutamol and has longer duration of activity (6 hours)

Question 14

How was salmeterol produced and how does it compare to salbutamol?

Answer 14

1. Nocturnal asthma was a problem that occurred around 4am which needed to be solved
2. A more lipophilic drug would bind more strongly to the tissue and act for a longer period of time
3. This was done by increase the length of the N- substituent with a further hydrocarbon chain and aromatic ring
4. Twice the potency of salbutamol and an extended action of 12 hours

Question 15

How is an anti-asthmatic drug reduced in terms of life time?

Answer 15

1. Most anti-asthmatic drugs are inhaled in the form of an inhaler to reduce the number of side effects in the body
2. However, it’s life time is reduced when a lot of it is swallowed and absorbed into the blood supply by the gastrointestinal tract

Question 16

What is the problem with an anti-asthmatic drug such as Cromakalim?

Answer 16

It has useful anti-asthmatic properties and is potent/stable but is easily metabolised in the blood stream to cause cardiovascular problems

Question 17

Describe the synthesis of salbutamol?

Answer 17

Step 1 – Friedel Craft acylation (Aspirin)
Step 2 – Esterification
Step 3 – Bromination
Step 4 – Nucleophilic substitution
Step 5 – Reduction
Step 6 - Hydrogenation (salbutamol)