43- h2 antagonists

Question 1

how many protonation sites does histamine have

Answer 1

2 and 7.4 this is the form thats most likely to bind to the receptor

Question 2

explain the receptor site of histamine

Answer 2

• left is neutral aromatic ring

- right side is positive = ionic bonds with the receptor

Question 3

what happens when you change the amine

Answer 3

if you change it to the larger group, it changes from an agonist to a partial agonist

Question 4

how do partial agonists work

Answer 4

• Agonist binds to receptor and produces non-ideal conformational change
  
  • Weak signal is sent (short duration)
• Agonist capable of binding to receptor in more than one way
  
  • One binding mode gives agonism
  • Other binding mode gives antagonism

Question 5

how can you explain the results that come with changing the amine

Answer 5

• positive charge is shared by all of the atoms = spread over a bigger volume

Question 6

what are the two binding modes for histamine to the receptor

Answer 6

• receptor agonist (small distance between pharmacophores)

- receptor antagonist (large distance between pharmacophores)

Question 7

what are the effects of adding a sulfur to a histamine

Answer 7

• Large atom does not form pi bonds easily
• Adding sulfur limits locations of S+
  
  • Forms with C=S make a very small contribution
  • even though there are electrons on the S, it will not do resonance

Question 8

what happens when the S is added directly in the histamine chain? what happens when it is added as a subsitutient

Answer 8

• with the sulfur at the location within the chain its only possible to get antagonist activity
• sulfur at any other location = partial agonist/antagonist

Question 9

what is the effect of increasing the chain length of histamine

Answer 9

pure antagonism (because of distance between the pharmacophores)

Question 10

how does the orientation of charge on the histamine affect the binding

Answer 10

• if the + is too far away from the receptor = inactive

- if the + is close to the receptor = antagonist

Question 11

what happens when an EWG is added to a histamine?

Answer 11

• prevents formation of positive charge within the histamine, but facilitates H-bonding between the histamine and receptor

Question 12

how can you control protonation of histamine

Answer 12

use a S or an EWG

Question 13

what will resonance forms help identify

Answer 13

protonation site on thioarginine.

- which spot is negative the most, that will be the protonation site

Question 14

what does ionic and h-bonding result in

Answer 14

antagonist

Question 15

what does only h-bonding result in

Answer 15

weak antagonist

Question 16

what does h-bonding and longer chain result in

Answer 16

antagonist

Question 17

how do you go from agonist to antagonist

Answer 17

look at diagram

Question 18

why does the histamine ring have to be neutral

Answer 18

at pH 7.4 , 97% of histamine molecules carry only one +ve charge. the neutral ring will bind best to the receptor

Question 19

why do you want to make the histamine ring less basic

Answer 19

want to keep the molecule neutral = add an EWG to prevent positively charged

Question 20

what is the first explanation for the effect of EWG

Answer 20

• EWG destabilizes positively charged form
• EWG pulls electrons out and the equilibrium will be shifted
• electron withdrawing group removes some electron density from the ring
• this increases the effective positive charge slightly
• the charged form becomes less stable
• equilibrium shifts towards neutral-ring form

Question 21

what is the second explanation for the effect of EWG

Answer 21

• EWG reduces a bases ability to donate electrons
• add EWG makes N less likely to donate electrons
• electron withdrawing group reduces ability of ring nitrogen to donate electrons
• the ring is now a weaker base
• equilibrium shifts towards neutral-ring form

Question 22

what is the effect of EWG on base strength

Answer 22

• NH3+ is a strong electron-withdrawing group (+ve charge)
• Ring in histamine is a weaker base
• pKa of histamine is lower than the mitosol
• at physiological pH it’s + charge pulls electrons out of the ring and destabilizes it

Question 23

why does adding a CH2 isostere make the histamine ring neutral

Answer 23

• replaced a CH2 with an isostere (O)
• C-O bond is shorter = shorten the distance = weak antagonist
• C-S bond is long = yay strong antagonist = strong antagonist
• increased activity by reducing the positive charge

Question 24

what does adding Me do to the histamine ring

Answer 24

improves binding by controlling rotamers

Question 25

what were the issues with the CH3 histamine

Answer 25

• Kidney damage
• Reduction in white cell counts
• Thioureas known to cause toxicity issues in other drugs
  
  • Replace thiourea with bio-isostere

Question 26

what is the best thiourea isostere

Answer 26

NCN

Question 27

what is tagamet

Answer 27

• first blockbuster drug

- reduces production of stomach acid

Question 28

outline the development of tagamet

Answer 28

• 1964 - SAR started
  
  • used rational drug design
• 1972 - Cimetidine synthesized
• 1976 – Tagamet marketed
• 1986 - $1 billion in annual sales
  
  • First drug to do this
• 1994 – patent expired
  
  • Sharp decline in sales
  • Generic versions available