Nick (Anti-asthma drugs)

Question 1

Endogenous adrenoreceptor agonists

Answer 1

Adrenaline and noradrenaline are classes as catecholamines and examples of endogenous adrenoreceptor agonists.

Question 2

Adrenaline would relieve asthma symptoms if administered so why is it not an ideal medication for someone suffering from asthma?

Answer 2

Not selective or specific so has other side effects e.g. increases heart rate. Its structure allows it to bind to other receptors particularly b1 adrenoreceptors which causes contraction in the heart tissue.

Question 3

Goal of asthma drugs

Answer 3

To design a drug that will selectively bind to the b2 adrenoreceptor over the alpha and b1 adrenoreceptors.

Question 4

What binding interactions will adrenaline form with the receptor?

Answer 4

The presence of OH groups can form hydrogen bonds to the receptor and the aromatic ring is likely to be involved in hydrophobic interaction (repulsive force).

Question 5

SAR’s (Structure activity relationship) of adrenaline

Answer 5

Essential structural features for activity:
1. -OH groups on the benzene ring involved in H-bonding. The meta OH group can be modified with other H-bonding groups
2. Alcohol group in the side involved in H-bonding
3. R enantiomer more active than the S enantiomer
4. Ionic bonding involved between the N+ and the negatively charged group on the receptor.
5. Larger substituents on the N increases selectivity for beta adrenoreceptors over alpha adrenoreceptors

Question 6

Drugs to treat asthma

Answer 6

One of the first drugs used was isoprenaline. The addition of a bulky isopropyl group introduces selectivity for beta-adrenoreceptors over alpha-adrenoreceptors.
(Binding site is a small hydrophobic pocket. Adding the isopropyl is detrimental to binding of alpha sites making it more selective.)

However, there is no selectivity between beta subtypes and this causes cardiovascular side effects due to also binding the b1 adrenoreceptor.
Addition of a ethyl group to the C bonded to the N shows selectivity for b2 adrenoreceptors.

This is short lasting as it is metabolised by the enzyme catechol-O- methyltransferase (COMT).
Adrenaline is short acting. It is metabolised by 2 enzymes. It can be made longer acting by inhibiting one of the enzymes.

Question 7

Metabolism of catecholamines

Answer 7

Noradrenaline metabolised by COMT which substitutes an OH on the benzene ring for a MeO group. This is metabolised by MAO (mono amine oxidase which replaces the NH2 group for a O=C-H. Finally there is an aldehyde functional group transformation which replaces the H with an OH.

Question 8

Why is adrenergic activity lost after metabolism by the COMT?

Answer 8

The loss of the H-bond donor in adrenaline means activity is lost.
Issue- making OH resistant to metabolism.

Question 9

Salbutamol

Answer 9

The addition of the hydroxymethyl group (-CH2OH) retains b2 agonist activity but not recognised by COMT enzyme.
Salbutamol has the same potency as isoprenaline but 2000 times less active on the heart.

Question 10

Fries rearrangement

Answer 10

This is a rearrangement reaction of a phenolic ester to a hydroxyl aryl ketone.
The acyl group (RCO) swaps places with a hydrogen

Question 11

Esterification

Answer 11

Formation of an ester by reacting an alcohol with a carboxylic acid.
Alcohol + carboxylic acid –> ester + water.

Question 12

Bromination

Answer 12

The alpha hydrogen of the ketone is acidic. Once this is lost the Br can add via an electrophilic addition mechanism

Question 13

Nucleophilic substitution

Answer 13

Reaction of an amine with an alkyl halide.

Question 14

Reduction

Answer 14

LiAlH4 is used as a reducing agent and reduces a ketone to a secondary alcohol.
It also reduces an ester to two primary alcohols.

Question 15

Hydrogenolysis

Answer 15

Reaction where a carbon-carbon or carbon-heteroatom (e.g. N) single bond is broken by hydrogen (H2).

Question 16

Other drugs used to treat asthma

Answer 16

Salmeterol is a longer acting drug used for nocturnal asthma. It has increased lipophilicity due to the presence of large hydrophobic group.
The hydrophobic side chain contains an ether. This is required for activity as the oxygen acts as a hydrogen bond acceptor.

Question 17

Non-steroidal drug summary points

Answer 17

The important binding groups in catecholamines are the 2 phenol groups, the aromatic ring, the secondary alcohol, and the ionised amine.
Placing bulky groups on the amine leads to selectivity for b-receptors over a-receptors.
Agents which are selective for b2 adrenoreceptors are useful anti-asthmatic agents.
Early b2 agonists were metabolised by COMT. Replacing the susceptible phenol group with a hydroxymethyl group prevented metabolism while retaining receptor interactions.
Longer lasting anti-asthmatics can be obtained by increasing the lipophilicity of the compounds.

Question 18

Steroids

Answer 18

Have a basic tetracycline structure.
Important endogenous hormones. One classification is adrenocorticoids. These are steroids released from the adrenal cortex of the adrenal gland.
There are two types of adrenocorticoid; glucocorticoids and mineralocorticoids.
Mineralocorticoids regulate electrolyte balance through sodium ion retention in the kidney cells.
Glucocorticoids have many important functions including inflammatory effects.

Question 19

Structure of steroids

Answer 19

All steroids share a tetracyclic structure, but they vary in the substituents and functional groups present.
The major endogenous glucocovrticosteroids are corticosterone, cortisol (hydrocortisone- has a H where the =O is in cortisone), and cortisone.

Question 20

Increasing the activity of glucocorticoids

Answer 20

Cortisol is the lead compound for steroidal anti-inflammatory drugs. All functional groups in cortisol are important for activity:
- Three alcohol groups
- Ketone in the side chain
- a.b-unsaturated ketone

Some groups/substituents can be added to increase activity.
- Adding a halide at C9 increases activity
- Adding a C=C between C1 and C2 increases activity
- Adding a methyl group at C16 suppresses mineralocorticoid side effects

This led to the synthesis of many analogues of cortisol including beclomethasone-17-21-dipropionate a drug currently used as an asthma inhaler.

Question 21

Other steroidal drugs based on similar structures

Answer 21

Budesonide
Cliclesonide
Mometasone furoate
Fluticasone propionate

Beclomethasone is a pro-drug so will be modified. The ester is hydrolysed to an alcohol. This is why it can show activity without having the specific functional groups needed for activity.

Question 22

Steroidal drugs summary points

Answer 22

All steroids have a basic tetracycline structure.
Endogenous adrenocorticoids include glucocorticoids and mineralocorticoids. Glucocorticoids have anti-inflammatory effects.
Cortisol is the lead compound for steroidal anti-inflammatories.
All the functional groups in cortisol are important for activity.
Functional groups/substituents can be added to increase activity