Opioids Messge Flashcards
Address
Confirs selectivity for a particular subtype
Message
Component of the ligand that defines primary receptor recognition (eg to a receptor family)
NorBNI is essentially two
Naltrexones
MesonorBMI
Is a mirror image, both the rings come OUT of the page
Inverted stereochemistry of address
Left/right is the m or a
Left is the message, right is the address
Nor BMI is … Selective
Mew and kappa antag
Meso nor BMI is …
Selective kappa antagonist
So the address is different by they are acting on the same receptor? Why ???
Basic nitrogens sit in the same place, you can strip away everything else and it still works
Kappa pharmacophore consists …
Opioid message
Address: spacer+2nd basic nitrogen or other cation (interacts with glutamic acid in side chain)
Delta pharmacophore
Opioid.message
Address: spacer and aromatic ring
(Found on NTI)
Can the delta antagonist be converted into a kappa antagonist by making use of the kappa antagonist pharmacophore?
Yes. Use a guanadine after the aromatic ring. Has three basic atoms so covers a wide area
Why do we have some scope with the basic group
The proton in the N that is shared with the acidic group in the receptor has to be in the right place, not the actual N molecule
What potent kappa antagonist is produced from combining the delta and kappa addresses
GNTI (has the guanadine)
Four main ways to alter the opioids
Change N-substituent for differing efficacies; (agonist – partial agonist – antagonist)
Change C3-substituent to change potency and pharmokinetic properties
Use of side chains (e.g. in orvinols) to change efficacy
Use message-address principle to access selective ligands
Most ligands have had the phenylpiperidine motif with the phenyl ring in an …. configuration
Axial
What happens if we have an equatorial ligand?
N protons still reach to interact in same places so you get efficacy
But you only get antagonists as the r groups extent to different area of space
If the N-substituent in this new series of phenylpiperidines does not influence the efficacy of the ligands (they are all antagonists), then perhaps it could be used to …
influence potency and selectivity and pharmacokinetic properties
Why?major sideeffect is GI sideeffects such as constipation in a hospital setting. So if you could develop and antagonist that works in the perifery maybe you could combat this and administer with morphie
How to stop something crossing the BBB
Make it highly charged like a zwitter ion
What is being developed by Glaxo as a preventative agent for the GI problems associated with opioid pain relief after surgery
Alvimopa
At physiological pH become a zwitter ion so does not cross the BBB
JDTic was developed by
Combinatorial chemistry of library of phenylpiperidine series
JDTic acts how
highly potent a selective antagonist for kappa opioid receptors.
JDTic is even more confusing becuase
It binds in reverse
The n of the receptor binds to the message
