43- h2 antagonists Flashcards
how many protonation sites does histamine have
2 and 7.4 this is the form thats most likely to bind to the receptor
explain the receptor site of histamine
- left is neutral aromatic ring
- right side is positive = ionic bonds with the receptor
what happens when you change the amine
if you change it to the larger group, it changes from an agonist to a partial agonist
how do partial agonists work
- 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
how can you explain the results that come with changing the amine
- positive charge is shared by all of the atoms = spread over a bigger volume
what are the two binding modes for histamine to the receptor
- receptor agonist (small distance between pharmacophores)
- receptor antagonist (large distance between pharmacophores)
what are the effects of adding a sulfur to a histamine
- 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
what happens when the S is added directly in the histamine chain? what happens when it is added as a subsitutient
- with the sulfur at the location within the chain its only possible to get antagonist activity
- sulfur at any other location = partial agonist/antagonist
what is the effect of increasing the chain length of histamine
pure antagonism (because of distance between the pharmacophores)
how does the orientation of charge on the histamine affect the binding
- if the + is too far away from the receptor = inactive
- if the + is close to the receptor = antagonist
what happens when an EWG is added to a histamine?
- prevents formation of positive charge within the histamine, but facilitates H-bonding between the histamine and receptor
how can you control protonation of histamine
use a S or an EWG
what will resonance forms help identify
protonation site on thioarginine.
- which spot is negative the most, that will be the protonation site
what does ionic and h-bonding result in
antagonist
what does only h-bonding result in
weak antagonist
what does h-bonding and longer chain result in
antagonist
how do you go from agonist to antagonist
look at diagram
why does the histamine ring have to be neutral
at pH 7.4 , 97% of histamine molecules carry only one +ve charge. the neutral ring will bind best to the receptor
why do you want to make the histamine ring less basic
want to keep the molecule neutral = add an EWG to prevent positively charged
what is the first explanation for the effect of EWG
- 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
what is the second explanation for the effect of EWG
- 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
what is the effect of EWG on base strength
- 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
why does adding a CH2 isostere make the histamine ring neutral
- 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
what does adding Me do to the histamine ring
improves binding by controlling rotamers
what were the issues with the CH3 histamine
- Kidney damage
- Reduction in white cell counts
- Thioureas known to cause toxicity issues in other drugs
- Replace thiourea with bio-isostere
what is the best thiourea isostere
NCN
what is tagamet
- first blockbuster drug
- reduces production of stomach acid
outline the development of tagamet
- 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
