H2RA

Question 1

What is a pharmacophore?

Answer 1

optimum molecular features for biological activity
- e.g. benzodiazepine binding site on a GABAa receptor

Question 2

What is a bioisostere?

Answer 2

a replacement group (or molecule) that produces a similar biological effect to the original

Question 3

What are the defining groups on cimetidine, ranitidine, famotidine and nizatidine?

What are their brand names?

Answer 3

cimetidine - has a cyano group in the long chain
= Tagamet

ranitidine - has a furan ring
= Zantac

famotidine - has a sulfamoyl group in the long chain
= Pepcid

nizatidine - has a nitrothiazide ring
= Axid

Question 4

What are the possible interactions for the H2RAs?

Answer 4

cimetidine - inhibits hepatic cytochrome P450
= potentiates drugs metabolised by oxidation including warfarin, phenytoin, theophylline, alcohol

ranitidine - has little effect on CYP450s

famotidine and nizatidine - have no effect on CYP450s

Question 5

What are the side effects of all H2RAs? What side effects are specific to cimetidine?

Answer 5

all H2RAs - diarrhoea, headache

cimetidine - somnolence, gynaecomastia, sexual dysfunction
= crosses the blood brain barrier

in less than 1% of cases bone marrow is affected resulting in thrombocytopenia (reduced platelets)
- for all the drugs

Question 6

What is the difference between agonists, antagonists and inverse agonists?

Which are H2RAs and why?

Answer 6

agonists - increase activity
= increased release

antagonists - inherent activity
= acts as a dimmer, low level release

inverse agonists - decreases activity
= reduced release

OTC H2RAs are inverse agonists due to constitutive activity of H2 receptors

Question 7

What is random screening strategy?

What are the disadvantages?

Answer 7

random screening strategy is when drugs are developed by testing thousands of natural compounds

disadvantages
- can be unsuccessful and it does not show why
- is slow and expensive with a high failure rate

Question 8

What is rational drug design?

Answer 8

designing drugs using an understanding of the interaction between ligands and the receptors
- generates a lead that can be improved to give a new lead, etc

Question 9

What are the types of rational drug design?

Answer 9

pharmacophore based approach
- studies a working model of a ligand

structure based approach
- studies a working model of a active site

Question 10

What are the tautomers of metiamide?

Answer 10

there are two possible tautomers - N tau and N pi

the N tau tautomer is active
- we want the top N-H to be more basic so it can protonate
- we want the bottom N to be less basic so it will not protonate

Question 11

What is the purpose of CH3 and S groups in the tautomers of metiamide?

Answer 11

CH3 is an electron donating group
- makes the top NH more basic and promotes protonation
= keeps it in the N tau tautomer and makes the N pi readily protonated back to N tau

S is an electron withdrawing group
- makes the bottom N group less basic and less readily protonated
= keeps it in the N tau tautomer and makes N tau less likely to lose a proton to form N pi

Question 12

Why is the thiourea group toxic? What is it replaced with?

Answer 12

C=S is toxic because it causes agranulocytosis (reduced white blood cell count)

C=S is replaced with C=N-C=N bioisostere

Question 13

Which H2RA is the most potent?
Which H2RA is anticholinergic in cats and has carcinogenic impurities?
Which H2RA can exist in tautomeric forms?

Answer 13

famotidine

ranitidine

cimetidine

Question 14

How was cimetidine formed?

Answer 14

rational drug design using pharmacophore based approach