The tricyclic system
The piperazine ring
The aromatic ring
The imidazole ring
It acts as a transition-state isostere.
It binds to the zinc ion cofactor.
It binds to a binding sub pocket in the active site.
It acts as a steric shield.
All three nitrogens are fully ionised
All three nitrogens are not ionised at all
The side chain nitrogen is fully ionised and the heterocyclic nitrogens are not ionised
The side chain nitrogen and one of the heterocyclic nitrogens are fully ionised
There is a binding region for the imidazole ring of histamine analogues which is common for agonists and antagonists.
There is a binding region which interacts ionically with the α-nitrogen of histamine and results in agonist activity.
There is a binding region further away from the imidazole ring that produces an antagonist effect if occupied.
The α-nitrogen of histamine can only bind to the agonist binding region while the guanyl group of Nα-guanylhistamine can only bind to the antagonist binding region.
It established the existence of H2-receptors
It was a good antagonist at H2 receptors with only weak partial agonist activity
It inhibited gastric acid release from parietal cells
It indicated that binding to the antagonist binding region involved hydrogen bonding and not ionic bonding
It introduced an extra binding interaction
It stabilised the molecule
It increased the percentage population of the active heterocyclic tautomer
It prevented ionisation of the terminal functional group
To block metabolism at that region of the heterocyclic ring
To introduce a group which would be metabolised in a predictable fashion
To introduce an electron withdrawing group on the heterocyclic ring to reduce the chance of ionisation
To introduce an electron donating group on the heterocyclic ring to favour the active tautomer
To introduce a basic group which could ionise and allow ionic interactions with the binding region.
To replace an unnatural functional group with a naturally occurring group in order to reduce side effects.
To increase the number of hydrogen bond donors present to acquire extra binding interactions.
To change the geometry and stereochemistry of the functional group such that it fitted the binding region more closely.
It is an electron donating group and increases the basicity of the functional group such that it protonates and becomes ionised.
It is an electron withdrawing group and increases the basicity of the functional group such that it protonates and becomes ionised.
It is an electron donating group and decreases the basicity of the functional group such that it does not become protonated and remains un-ionised.
It is an electron withdrawing group and decreases the basicity of the functional group such that it does not become protonated and remains un-ionised.
A and B
A and C
B and D
A and D
EZ and ZE. It proved the chelation theory of hydrogen bonding.
EZ and ZZ. It established that there was only one hydrogen bonding interaction with the receptor in this region.
EE and ZZ. It established that there were two hydrogen bonding interactions to different groups within the same binding region.
EE and ZE. No conclusions could be drawn.