Hypertensives

Question 1

ACE is what kind of peptidase?

Answer 1

Non selective

Question 2

Where does ACE cleave?

Answer 2

On the last two amino acids from many peptides

Question 3

Where does ACE not cleave?

Answer 3

On peptide in which the second last amino acid is PROLINE

Question 4

How many amino acid does angiotensin 1 have?

Answer 4

10 amino acids

Question 5

How many amino acids does Angiotensin 2 have?

Answer 5

8 amino acids, the second last amino acid is proline

Question 6

what is the name of the snake where the scientists got the venom from?

Answer 6

Bothrops Jararaca

Question 7

What does the venom do.?

Answer 7

Decrease BP, Can cause death

It inhibits ACE

Question 8

What is the name of the peptide isolated from the venom?

Answer 8

Teprotide

Question 9

Why is teprotide not good?

Answer 9

Because it is not orally active

Second amino acid is proline

Question 10

How is ACE and carboxypeptidase similar?

Answer 10

They both need Zn2+ for activity, both are peptides

Question 11

What is the inhibitor of carboxypeptidase A?

Answer 11

D-2-benzylsuccinic acid

Question 12

How to make D-2-methylsuccinic proline

from D-2-benzylsuccinic acid?

Answer 12

Add proline group to make ACE recognise it
👉 succinyl-proline
increase the chain length by adding a methyl like the dipeptides
👉 D-2-methylsuccinic proline

Question 13

How to make captopril

Answer 13

add THIOL GROUP to D-2-methyl succinic proline

Change COOH to -SH which can act as Zn2+ ligand,
Interacting with positive

Question 14

CAPTOPRIL SARs

Answer 14

Methyl : increased potency 20x

Thiol: increase potency x1000

Question 15

Any possible modification to captopril

Answer 15

Addition of S in 5-ring 👉 thioproline

Addition of benzene to the 5-ring (benzofusion) 👉 increase potency 3-7x

Question 16

When can captopril be inactive?

Answer 16

When benzene ring is added too close to the COOH

👉 steric hindrance

Question 17

Some limitation of captopril caused by SH (thiol)

Answer 17

Rash, change/loss of taste

Question 18

What is the ACEI without the thiol group

Answer 18

Enalapril

Question 19

How to make enalaprilat from D-2-methylsuccinyl pro?

Answer 19

Add amine (NH) to make it more like a peptide
Add silicon/ benzene to make it more lipophilic

Question 20

Is enalaprilat a good ACEI?

Answer 20

No, it is very polar due to too many charges (too much ionisation by 2 x COOH and NH)

👉👉add an ester to the top COOH. And make it enalapril (prodrug)

Question 21

Enalapril and enalaprilat ionisation difference

Answer 21

Enalapril - pKa (NH) ~5.5
Less ionised at physiological pH, non polar, orally active

Enalaprilat - pKa (NH) ~7.6
More ionised, very polar, orally inactive

Question 22

Enalapril SARS

Answer 22

S1- amine ring and COOH (needed for activity)
S2 - methyl group
S3 - benzene ring

Question 23

When does enalapril lose activity?

Answer 23

S1
When proline is removed 
When COOH is converted to amide
S3
When branching on a-carbon (2 carbons away from benzene)
When addition of acidic side chain
S2
When any carbon branching (steric hindrance)
When addition of acidic side chain

Question 24

How to make indolapril?

Answer 24

From enalapril, on s1, add 6-ring onto the amine ring (retained activity)

Question 25

Any fine modification on captopril

Answer 25

On s3- modification of aliphatic and aromatic rings On s2- many side chains All retain activity

Question 26

How to make Lisinopril

Answer 26

S2= (CH2)4 NH2 Do not need to convert to ester Because lisinopril is a Di-zwitterion in the duodenum pH It forms ion pairs and can cross membrane together 👉 orally active

Question 27

What is the first ARB made from?

Answer 27

Takes a lead | based on “imidazole-­‐5-­‐acetic acid analogues” – patent filed

Question 28

What did DuPont Merck do to make a different ARB?

Answer 28

Tried to make a new one based on peptide inhibitor but failed Looked at what the takeda lead contained to mimic ang2 and what the takeda lead was missing DEVELOPED LOSARTAN

Question 29

What does takeda lead have that mimic the ang 2?

Answer 29

1)   C-­‐terminus carboxylate ion (on the right end) 2)   Imidazole ring (between carboxylate ion and butyl group, at the bottom) 3)   n-­‐butyl group of S-­‐8038 similar to isoleucine side chain of Ang II (in the middle on top)

Question 30

What was takeda lead missing?

Answer 30

Acidic side chain on the N terminus Good interaction on the C terminus but barely any interaction on the N

Question 31

Big breakthrough in developing ARB from takeda lead

Answer 31

Addition of acidic group (COOH) on the benzene ring

Question 32

How to make losartan?

Answer 32

Through further modification to takeda lead including addition of acidic group 👉👉 tetrazole group on the benzene ring (mimicking the COOH group, the negative charge)

Question 33

One example of losartan analogues | And what does it need?

Answer 33

Valsartan | It needs ester groups (pro drugs need to be hydrolysed to become active)

Question 34

Other improvements on takeda lead

Answer 34

Instead of focusing on the missing acidic group on n terminus, Focus on mimicking the c terminus as much as possible 👉Eprosartan

Question 35

Activation of beta-1 adrenergic receptor leads to...

Answer 35

Increase rate and force of cardiac contractions | Increase blood pressure

Question 36

Activation of beta-2 adrenergic receptors leads to...

Answer 36

Bronchodilation

Question 37

What are the two types of non-selective beta adrenergic receptor blockers?

Answer 37

Arylethanolamine type e.g. Sotalol | Aryloxypropanolamine type e.g. Propranolol

Question 38

What is the general rule of selective beta-1 adrenergic receptor blocker?

Answer 38

4-(para) substituted phenoxypropanolamines | If 3-substituted, it is non-selective

Question 39

What stops the alpha-activity of other beta-blockers? | What is lacked in the mixed alpha/beta adrenergic blockers?

Answer 39

N substituents

Question 40

What are the examples of mixed alpha and beta blockers

Answer 40

Carvedilol and labetalol

Question 41

What are the examples of selective beta 1 receptor blockers?

Answer 41

Atenolol, metoprolol

Question 42

What are the examples of non selective betablockers

Answer 42

Sotalol, propranolol

Question 43

What happens if you activate alpha receptor

Answer 43

Vasoconstriction

Question 44

What is the non selective AGENT of alpha blocker?

Answer 44

Phenoxybenzamine

Question 45

What is the stable salt form of phenoxybenzamine?

Answer 45

``` Aziridinium ion (high reactive in water) It reacts with nucleophile group (S,N,O) of an amino acid on an alpha receptor. ```

Question 46

What is the name of the receptor when the drug is covalently bonded to the alpha receptor?

Answer 46

Alkylated receptor

Question 47

What is the duration of action of phenoxybenzamine?

Answer 47

Very long acting Because the drug is stuck to the receptor and the only way to get rid of this effect is to make a new receptor (as the receptor is alkylated)

Question 48

What is phenoxybenzamine used for?

Answer 48

To relieve symptoms of some adrenal tumours that secrete large amounts of A and NA

Question 49

What is the classic a1 selective antagonist? | And what aromatic ring does it contain?

Answer 49

Prazosin | Quinozoline (two 6-rings together), aliphatic 6-ring, furan ring (5-ring with oxygen)

Question 50

How do you increase duration of action in a1 selective antagonist?

Answer 50

Reduce the furan ring (From double bond to single bond)

Question 51

Centrally acting agents are what type of receptor agonist?

Answer 51

A2 adrenergic receptor

Question 52

What happens if you activate A2 receptor?

Answer 52

Decrease in BP --> antihypertensive

Question 53

Where else can a1 agonist be used for?

Answer 53

Nasal decongestant

Question 54

What are examples of centrally acting agent? - a2 agonist

Answer 54

Clonidine (classic), guanabenz, a-methyl norepinephrine (prodrug is methyldopa)

Question 55

What is important in a way clonidine acts?

Answer 55

Conformation and ring orientation

Question 56

Does methyldopa cross BBB

Answer 56

Yes

Question 57

What do CCB target in the cells?

Answer 57

L- type calcium channels

Question 58

What are the chemical classes in CCB?

Answer 58

Dihydropyridine eg. Amlodipine Phenylalkyamines eg. Verapamil (OFTEN SYMMETRICAL) Benzothiazipines eg. Diltiazem (Sulfur in the ring) Diaminopropanol eg. Bepridil (rare)

Question 59

What is special about dihydropyridines?

Answer 59

Subtle changes in structure can change properties You can make it a calcium channel activator (Swapping CO2CH3 in isradipine to NO2)

Question 60

Dihydropyridines SARS

Answer 60

Substituted phenyl ring at the C4 position optimises activity Ortho or meta substituents increase activity PARA or None substituents decrease activity